PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity.

Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers comprised of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of PGC-1α, a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNC types. PGC-1α correlated tightly with increased expression of the lineage marker ASCL1 through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. PGC-1α overexpression enhanced OXPHOS, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These findings reveal the metabolic heterogeneity among SCNC subtypes and identify PGC-1α-induced OXPHOS as a regulator of SCNC lineage plasticity.

Single-Layer Hexagonal Boron Nitride Nanopores as High-Performance Ionic Gradient Power Generators.

Atomically thin two-dimensional (2D) materials have emerged as promising candidates for efficient energy harvesting from ionic gradients. However, the exploration of robust 2D atomically thin nanopore membranes, which hold sufficient ionic selectivity and high ion permeability, remains challenging. Here, the single-layer hexagonal boron nitride (hBN) nanopores are demonstrated as various high-performance ion-gradient nanopower harvesters. Benefiting from the ultrathin atomic thickness and large surface charge (also a large Dukhin number), the hBN nanopore can realize fast proton transport while maintaining excellent cation selectivity even in highly acidic environments. Therefore, a single hBN nanopore achieves the pure osmosis-driven proton-gradient power up to ≈3 nW under 1000-fold ionic gradient. In addition, the robustness of hBN membranes in extreme pH conditions allows the ionic gradient power generation from acid-base neutralization. Utilizing 1 m HCl/KOH, the generated power can be promoted to an extraordinarily high level of ≈4.5 nW, over one magnitude higher than all existing ionic gradient power generators. The synergistic effects of ultrathin thickness, large surface charge, and excellent chemical inertness of 2D single-layer hBN render it a promising membrane candidate for harvesting ionic gradient powers, even under extreme pH conditions.

Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation.

Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans-differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states.

Chiroptical Response Inversion and Enhancement of Room-Temperature Exciton-Polaritons Using 2D Chirality in Perovskites.

Although chiral semiconductors have shown promising progress in direct circularly polarized light (CPL) detection and emission, they still face potential challenges. A chirality-switching mechanism or approach integrating two enantiomers is needed to discriminate the handedness of a given CPL; additionally, a large material volume is required for sufficient chiroptical interaction. These two requirements pose significant obstacles to the simplification and miniaturization of the devices. Here, room-temperature chiral polaritons fulfilling dual-handedness functions and exhibiting a more-than-two-order enhancement of the chiroptical signal are demonstrated, by embedding a 40 nm-thick perovskite film with a 2D chiroptical effect into a Fabry-Pérot cavity. By mixing chiral perovskites with different crystal structures, a pronounced 2D chiroptical effect is accomplished in the perovskite film, featured by an inverted chiroptical response for counter-propagating CPL. This inversion behavior matches the photonic handedness switch during CPL circulation in the Fabry-Pérot cavity, thus harvesting giant enhancement of the chiroptical response. Furthermore, affected by the unique quarter-wave-plate effects, the polariton emission achieves a chiral dissymmetry of ±4% (for the emission from the front and the back sides). The room-temperature polaritons with the strong dissymmetric chiroptical interaction shall have implications on a fundamental level and future on-chip applications for biomolecule analysis and quantum computing.

Association between children's home-schooling and parental psychological distress during the COVID-19 pandemic in Taiwan: Risk and protective factors in a multilevel approach.

BACKGROUND: The role home-schooling of children in parental mental health during the COVID-19 pandemic in Taiwan remains unknown. This study aimed to assess the association between parental psychological distress and home-schooling in a socio-ecological context during the peak of the first wave of the COVID-19 pandemic in Taiwan. METHODS: This was a prospective cohort study. In total, 902 parents (father: n = 206, mother: n = 696) who home-schooled children under 18 years of age were recruited by purposive sampling from 17 cities in Taiwan. Data were collected between 19 July and 30 September 2021 through a survey. Multilevel regression models were used to examine the association between parents' psychological distress and home-schooling considering the characteristics at the person and city levels. RESULTS: Parental psychological distress was positively associated with difficulty in setting up electronic devices and increased disputes between parents and children, and it was negatively associated with time management and increased time spent bonding with their children during home-schooling (Ps < 0.05). Parents who had a child with health conditions, lived in an extended family, worked from home, lived during the Level 3 alert level, and lived with a median/sporadic level of the COVID-19 community spread by city also reported greater psychological distress (Ps < 0.05). However, parents who had greater household family support reported less psychological distress (P < .05). CONCLUSIONS: Clinicians and policy makers must carefully consider parental mental health while home-schooling during the COVID-19 pandemic in a broader socio-ecological context. A focus is advised on the home-schooling experiences of parents and other risk and protective factors for parental psychological distress at the person and city levels, especially for those with children who require medical interventions and have a medical condition.

Urinary microRNA in Diabetic Kidney Disease: A Literature Review.

Diabetic kidney disease is the most common primary disease of end-stage kidney disease globally; however, a sensitive and accurate biomarker to predict this disease remains awaited. microRNAs are endogenous single-stranded noncoding RNAs that have intervened in different post-transcriptional regulations of various cellular biological functions. Previous literatures have reported its potential role in the pathophysiology of diabetic kidney disease, including regulation of Transforming Growth Factor-ß1-mediated fibrosis, extracellular matrix and cell adhesion proteins, cellular hypertrophy, growth factor, cytokine production, and redox system activation. Urinary microRNAs have emerged as a novel, non-invasive liquid biopsy for disease diagnosis. In this review, we describe the available experimental and clinical evidence of urinary microRNA in the context of diabetic kidney disease and discuss the future application of microRNA in routine practice.

MicroRNA-based signature for diagnosis and prognosis of colorectal cancer using residuum of fecal immunochemical test.

BACKGROUND: Colorectal cancer (CRC) is still among the most lethal and prevalent malignancies in the world. Despite continuous efforts, the diagnosis and prognosis of CRC have never been satisfying, especially the non-invasive assays. METHODS: Our study comprised three independent cohorts of 835 qualified stool samples. From 46 literature-identified miRNA candidates, four miRNA ratios were selected and developed into a miRNA-based signature after applied to the training and test sets. The clinical performances of this signature were further evaluated in the prospective cohorts. RESULTS: Four miRNA ratios with significant alterations and the highest discriminating power between the CRC and control groups in the training set were successfully validated in the test set. In the training dataset, combining these four miRNA ratios using a logistic regression model improved the area under the curve value to 0.821 and obtained a sensitivity of 73.6% and specificity of 78.9%. This miRNA signature showed consistent performances in the other two sample cohorts, with the highest sensitivity of 85.7% in the prospective cohort. Additionally, the higher miRNA signature was associated with worse disease-free survival (hazard ratio = 2.27) and overall survival (hazard ratio = 1.83) of CRC patients. For fecal immunochemical test (FIT)-positive populations, the positive predictive value for CRC detection in miRNA-positive subjects was 3.43-fold higher in the prospective cohort, compared to FIT alone. CONCLUSION: This stool miRNA signature is highly associated with poor outcome of CRC and can be added to FIT tests to help identify the most at-risk group to receive prompt colonoscopy examination.

Treatment outcomes of primary surgery versus chemoradiotherapy for T4 oropharyngeal cancers.

Concurrent chemoradiotherapy (CCRT) has been the standard of care for locally advanced diseases regardless of human papillomavirus infection status. Other treatment options include surgery followed by adjuvant therapy and induction chemotherapy followed by CCRT or radiotherapy. However, for locally advanced T4 laryngeal or hypopharyngeal diseases, surgery is preferred over CCRT. Given the improvement in the functional outcomes of surgery, examining the oncologic outcomes in OPSCC patients is critical. This study aimed to determine whether differences in overall survival (OS) exist between surgery and CCRT. Oropharyngeal cancer patients included in the cancer registry of our hospital from January 2014 to December 2018 were retrospectively analyzed. Patients with T4 disease who underwent curative treatment were identified. In this study, the primary and secondary outcomes were OS and disease-free survival (DFS), respectively. Potential confounding factors were also evaluated. Details regarding recurrence pattern were listed. From 2014 to 2018, 74 newly diagnosed oropharyngeal cancer patients were identified from our cancer registry database, 60 of whom satisfied our inclusion criteria. Our findings showed an OS of 25.5 months and DFS of 17.5 months. No significant difference in both of OS and DFS were observed between the surgery and CCRT cohorts. Sex, stage, second primary cancer, IC, and primary treatment were not correlated with DFS. Male sex was the only significant factor identified, with an HR of 0.2 for OS (95% confidence interval, 0.06-0.71). No significant difference in both OS and DFS were observed between the CCRT and surgery cohorts. CCRT remains the standard of care for locally advanced disease.

Spin-Polarized Photocatalytic CO2 Reduction of Mn-Doped Perovskite Nanoplates.

"Spin" has been recently reported as an important degree of electronic freedom to improve the performance of electrocatalysts and photocatalysts. This work demonstrates the manipulations of spin-polarized electrons in CsPbBr3 halide perovskite nanoplates (NPLs) to boost the photocatalytic CO2 reduction reaction (CO2RR) efficiencies by doping manganese cations (Mn2+) and applying an external magnetic field. Mn-doped CsPbBr3 (Mn-CsPbBr3) NPLs exhibit an outstanding photocatalytic CO2RR compared to pristine CsPbBr3 NPLs due to creating spin-polarized electrons after Mn doping. Notably, the photocatalytic CO2RR of Mn-CsPbBr3 NPLs is significantly enhanced by applying an external magnetic field. Mn-CsPbBr3 NPLs exhibit 5.7 times improved performance of photocatalytic CO2RR under a magnetic field of 300 mT with a permanent magnet compared to pristine CsPbBr3 NPLs. The corresponding mechanism is systematically investigated by magnetic circular dichroism spectroscopy, ultrafast transient absorption spectroscopy, and density functional theory simulation. The origin of enhanced photocatalytic CO2RR efficiencies of Mn-CsPbBr3 NPLs is due to the increased number of spin-polarized photoexcited carriers by synergistic doping of the magnetic elements and applying a magnetic field, resulting in prolonged carrier lifetime and suppressed charge recombination. Our result shows that manipulating spin-polarized electrons in photocatalytic semiconductors provides an effective strategy to boost photocatalytic CO2RR efficiencies.

Design and Implementation of a Comprehensive AI Dashboard for Real-Time Prediction of Adverse Prognosis of ED Patients.

The emergency department (ED) is at the forefront of medical care, and the medical team needs to make outright judgments and treatment decisions under time constraints. Thus, knowing how to make personalized and precise predictions is a very challenging task. With the advancement of artificial intelligence (AI) technology, Chi Mei Medical Center (CMMC) adopted AI, the Internet of Things (IoT), and interaction technologies to establish diverse prognosis prediction models for eight diseases based on the ED electronic medical records of three branch hospitals. CMMC integrated these predictive models to form a digital AI dashboard, showing the risk status of all ED patients diagnosed with any of these eight diseases. This study first explored the methodology of CMMC's AI development and proposed a four-tier AI dashboard architecture for ED implementation. The AI dashboard's ease of use, usefulness, and acceptance was also strongly affirmed by the ED medical staff. The ED AI dashboard is an effective tool in the implementation of real-time risk monitoring of patients in the ED and could improve the quality of care as a part of best practice. Based on the results of this study, it is suggested that healthcare institutions thoughtfully consider tailoring their ED dashboard designs to adapt to their unique workflows and environments.

Hydrogel Arrays Enable Increased Throughput for Screening Effects of Matrix Components and Therapeutics in 3D Tumor Models.

Cell-matrix interactions mediate complex physiological processes through biochemical, mechanical, and geometrical cues, influencing pathological changes and therapeutic responses. Accounting for matrix effects earlier in the drug development pipeline is expected to increase the likelihood of clinical success of novel therapeutics. Biomaterial-based strategies recapitulating specific tissue microenvironments in 3D cell culture exist but integrating these with the 2D culture methods primarily used for drug screening has been challenging. Thus, the protocol presented here details the development of methods for 3D culture within miniaturized biomaterial matrices in a multi-well plate format to facilitate integration with existing drug screening pipelines and conventional assays for cell viability. Since the matrix features critical for preserving clinically relevant phenotypes in cultured cells are expected to be highly tissue- and disease-specific, combinatorial screening of matrix parameters will be necessary to identify appropriate conditions for specific applications. The methods described here use a miniaturized culture format to assess cancer cell responses to orthogonal variation of matrix mechanics and ligand presentation. Specifically, this study demonstrates the use of this platform to investigate the effects of matrix parameters on the responses of patient-derived glioblastoma (GBM) cells to chemotherapy.

Physical and in silico immunopeptidomic profiling of a cancer antigen prostatic acid phosphatase reveals targets enabling TCR isolation.

Tissue-specific antigens can serve as targets for adoptive T cell transfer-based cancer immunotherapy. Recognition of tumor by T cells is mediated by interaction between peptide-major histocompatibility complexes (pMHCs) and T cell receptors (TCRs). Revealing the identity of peptides bound to MHC is critical in discovering cognate TCRs and predicting potential toxicity. We performed multimodal immunopeptidomic analyses for human prostatic acid phosphatase (PAP), a well-recognized tissue antigen. Three physical methods, including mild acid elution, coimmunoprecipitation, and secreted MHC precipitation, were used to capture a thorough signature of PAP on HLA-A*02:01. Eleven PAP peptides that are potentially A*02:01-restricted were identified, including five predicted strong binders by NetMHCpan 4.0. Peripheral blood mononuclear cells (PBMCs) from more than 20 healthy donors were screened with the PAP peptides. Seven cognate TCRs were isolated which can recognize three distinct epitopes when expressed in PBMCs. One TCR shows reactivity toward cell lines expressing both full-length PAP and HLA-A*02:01. Our results show that a combined multimodal immunopeptidomic approach is productive in revealing target peptides and defining the cloned TCR sequences reactive with prostatic acid phosphatase epitopes.

Early diagnosis of Gitelman syndrome in a young child: A case report.

BACKGROUND: Gitelman syndrome (GS) is an autosomal recessive renal tubular disorder characterized by renal wasting hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. It is usually caused by mutations in the gene SLC12A3, which encodes the thiazide-sensitive Na-Cl cotransporter. GS is not usually diagnosed until late childhood or adulthood. CASE SUMMARY: Here, we report the case of a one-year-old girl who was brought to the emergency department due to persistent vomiting for two days. On admission to our hospital, generalized weakness was observed, and laboratory investigations revealed severe hypokalemia (1.9 mmol/L). However, persistent hypokalemia was observed during outpatient follow-up. Suspicion of the GS phenotype was assessed via the patient's clinical presentation, family history, and biochemical analysis of blood and urine. Further genetic analysis was performed for her and her family by exon-wide sequencing analysis of the gene SLC12A3. The genetic diagnosis of GS was established in the Taiwanese family with three affected individuals, two of whom were children (7 years/17 years) without obvious symptoms, with the youngest being only one year old (patient in our case). CONCLUSION: We successfully demonstrated the early diagnosis of GS using family genetic analysis. Any instances of hypokalemia should not be neglected, as early detection of GS with suitable treatment can prevent patients from potentially life-threatening complications.

Stabilized High-Membered and Phase-Pure 2D All Inorganic Ruddlesden-Popper Halide Perovskites Nanocrystals as Photocatalysts for the CO2 Reduction Reaction.

In contrast to the 2D organic-inorganic hybrid Ruddlesden-Popper halide perovskites (RPP), a new class of 2D all inorganic RPP (IRPP) has been recently proposed by substituting the organic spacers with an optimal inorganic alternative of cesium cations (Cs+ ). Nevertheless, the synthesis of high-membered 2D IRPPs (n > 1) has been a very challenging task because the Cs+ need to act as both spacers and A-site cations simultaneously. This work presents the successful synthesis of stable phase-pure high-membered 2D IRPPs of Csn+1 Pbn Br3n+1 nanosheets (NSs) with n = 3 and 4 by employing the strategy of using additional strong binding bidentate ligands. The structures of the 2D IRPPs (n = 3 and 4) NSs are confirmed by powder X-ray diffraction and high-resolution aberration-corrected scanning transmission electron microscope measurements. These 2D IRPPs NSs exhibit a strong quantum confinement effect with tunable absorption and emission in the visible light range by varying their n values, attributed to their inherent 2D quantum-well structure. The superior structural and optical stability of the phase-pure high-membered 2D IRPPs make them a promising candidate as photocatalysts in CO2 reduction reactions with outstanding photocatalytic performance and long-term stability.

Internal Built-In Electric Fields at Organic-Inorganic Interfaces of Two-Dimensional Ruddlesden-Popper Perovskite Single Crystals.

Two-dimensional (2D) organic-inorganic hybrid Ruddlesden-Popper perovskites (OIRPPs), which consist of naturally formed "multiple quantum well (MQW)-like" structure, have received considerable interest in optoelectronic applications, owing to their outstanding optical properties and tailorable functionalities. While the quantum-confined electrons and holes at an MQW structure are under an applied electric field, the tilt of the energy bands may cause a significant influence on their optical properties. This work demonstrates the presence of internal built-in electric fields (BIEFs) at the as-synthesized 2D OIRPP single crystals. Spontaneous Franz-Keldysh oscillations, which usually act as the fingerprint to account for the presence of BIEFs in the MQW-like structures, are observed at 2D OIRPPs by the highly sensitive differential technique of modulated thermoreflectance spectroscopy. The strength of BIEFs at 2D OIRPP single crystals reduces with increased n values due to the increased width of the quantum well. The origin of the presence of BIEFs at 2D OIRPPs is further unveiled by atomically resolved scanning tunneling microscopy on their electronic band structures at organic-inorganic interfaces. Unlike the conventional III-V MQW semiconductors with the BIEFs, which are dominated by the spatial concentration gradients at heterointerfaces, the presence of BIEFs at the 2D OIRPP single crystals is attributed to the molecular dipoles within organic spacers pointing to the organic-inorganic interfaces. The discovery of internal BIEFs at the 2D OIRPPs may provide deep insight into understanding the fundamental optical properties for the future design of large-area and low-cost perovskite optoelectronic devices.

Perihippocampal failure after hippocampal-avoidance whole-brain radiotherapy in cancer patients with brain metastases: Results of a retrospective analysis.

ABSTRACT: Perihippocampal failure is a rare clinical scenario in brain metastatic cancer patients following hippocampal-avoidance (HA) whole-brain radiotherapy (HA-WBRT). The clinical features have not been fully identified because clinical data on intracranial failure after HA-WBRT are limited. It is thus necessary to accumulate clinical data.We retrospectively analyzed cancer patients with brain metastases who were diagnosed between January 2014 and September 2020 at a regional referral hospital. The medical records of patients who underwent HA-WBRT were reviewed. The clinical features of intracranial recurrence were described. Dosimetry parameters were compared in terms of deviation from the recommended protocol of the Radiation Therapy Oncology Report 0933.Twenty-four eligible patients with brain metastases who underwent HA-WBRT were identified; 13 (54%) were male. Seventeen patients (71%) had lung cancer, 6 (25%) had breast cancer, and 1 (4%) had liver cancer. The median overall survival was 12 months. Three patients developed intracranial failure during clinical follow-up, and 2 relapsed with intracranial failure in the perihippocampal region at 13 and 22 months, respectively. The perihippocampal failure rate was about 8%. One patient with small cell lung cancer received HA-prophylactic cranial irradiation; the minimum and maximum doses to the hippocampi were 6.8 and 10.7 Gy, respectively. Another patient with brain metastases from lung adenocarcinoma received HA-WBRT; the minimum and maximum doses to the hippocampi were 5.4 and 10.6 Gy, respectively.We reported unusual cases of intracranial failure in the perihippocampal region following HA-WBRT. Perihippocampal failure could be attributed to an under-dose of radiation partially or be resulted from aggressiveness of cancer per se. Further research on this topic is encouraged.

Direct investigation of the reorientational dynamics of A-site cations in 2D organic-inorganic hybrid perovskite by solid-state NMR.

Limited methods are available for investigating the reorientational dynamics of A-site cations in two-dimensional organic-inorganic hybrid perovskites (2D OIHPs), which play a pivotal role in determining their physical properties. Here, we describe an approach to study the dynamics of A-site cations using solid-state NMR and stable isotope labelling. 2H NMR of 2D OIHPs incorporating methyl-d3-ammonium cations (d3-MA) reveals the existence of multiple modes of reorientational motions of MA. Rotational-echo double resonance (REDOR) NMR of 2D OIHPs incorporating 15N- and ¹³C-labeled methylammonium cations (13C,15N-MA) reflects the averaged dipolar coupling between the C and N nuclei undergoing different modes of motions. Our study reveals the interplay between the A-site cation dynamics and the structural rigidity of the organic spacers, so providing a molecular-level insight into the design of 2D OIHPs.

Serum microRNA panels predict bariatric surgery outcomes.

OBJECTIVE: The weight losses after bariatric surgery are modulated by multiple factors in people with obesity. MicroRNAs (miRNAs) have been reported to show significant regulatory roles in adipose tissue. However, a serum miRNA signature to serve as a biomarker of sustained weight losses following bariatric surgery has not yet been established. METHODS: MiRNA microarray was used to identify differentially expressed miRNAs in the serum of patients with an effective response after bariatric surgery compared with those without. Excess weight loss > 55% at 6 months after surgery was defined as an effective response. RESULTS: Three miRNAs were shown to have a significantly differential expression between patients with or without an effective response following bariatric surgery. The miR-31-5p was downregulated, whereas miR-328-3p and miR-181a-5p were upregulated in the patients with effective responses compared with those without effective responses. Panels of the serum ratios of miR-328-3p/miR-31-5p or miR-181a-5p/miR-31-5p and individual BMI value exhibited good performance in preoperative prediction of treatment effectiveness. Bioinformatic analysis depicted that predicted targets of these miRNAs were involved in the regulation of the AMP-activated protein kinase signaling pathway. CONCLUSIONS: A circulating miRNA signature with clinical variables (BMI) can be a clinical biomarker to predict effectiveness following bariatric surgery.