Decade-long leukaemia remissions with persistence of CD4+ CAR T cells.

The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1-7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1-4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.

PKC-ζ mediated reduction of the extracellular vesicles-associated TGF-ß1 overcomes radiotherapy resistance in breast cancer.

BACKGROUND: Radiotherapy is widely applied in breast cancer treatment, while radiotherapy resistance is inevitable. TGF-ß1 has been considered to be an endogenous factor for the development of radiotherapy resistance. As a large portion of TGF-ß1 is secreted in an extracellular vesicles-associated form (TGF-ß1EV), particularly in radiated tumors. Thus, the understanding of the regulation mechanisms and the immunosuppressive functions of TGF-ß1EV will pave a way for overcoming the radiotherapy resistance in cancer treatment. METHODS: The superoxide-Zinc-PKC-ζ-TGF-ß1EV pathway in breast cancer cells was identified through sequence alignments of different PKC isoforms, speculation and experimental confirmation. A series of functional and molecular studies were performed by quantitative real-time PCR, western blot and flow cytometry analysis. Mice survival and tumor growth were recorded. Student's t test or two-way ANOVA with correction was used for comparisons of groups. RESULTS: The radiotherapy resulted in an increased expression of the intratumoral TGF-ß1 and an enhanced infiltration of the Tregs in the breast cancer tissues. The intratumoral TGF-ß1 was found mainly in the extracellular vesicles associated form both in the murine breast cancer model and in the human lung cancer tissues. Furthermore, radiation induced more TGF-ß1EV secretion and higher percentage of Tregs by promoting the expression and phosphorylation of protein kinase C zeta (PKC-ζ). Importantly, we found that naringenin rather than 1D11 significantly improved radiotherapy efficacy with less side effects. Distinct from TGF-ß1 neutralizing antibody 1D11, the mechanism of naringenin was to downregulate the radiation-activated superoxide-Zinc-PKC-ζ-TGF-ß1EV pathway. CONCLUSIONS: The superoxide-zinc-PKC-ζ-TGF-ß1EV release pathway was elucidated to induce the accumulation of Tregs, resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-ß1EV function could represent a novel strategy to overcome radiotherapy resistance in the treatment of breast cancer or other cancers. TRIAL REGISTRATION: The using of patient tissues with malignant Non-Small Cell Lung Cancer (NSCLC) was approved by the ethics committees at Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (NCC2022C-702, from June 8th, 2022).

Ripple phenomenon and artifact elimination in millimeter-wave imaging of a hidden target.

In millimeter-wave imaging of a hidden target, the effect of the dielectric cover before the target is typically ignored. This results in ripple-corrupted images that pose challenges for target recognition. In this paper, we provide a perspective for understanding the image of the hidden target, which clearly reveals the origin of the ripples, and propose a separation method that not only gets rid of ripples, but also obtains the target's depth map. Reflections and transmissions during imaging are considered and decoupled to separately form images corresponding to each real or virtual object. An algorithm based on the range-direction spread function is developed to iteratively estimate the depth and reflectivity of the target. Imaging experiments with and without a cover are conducted to demonstrate the formation and influence of ripples and to verify the proposed algorithm. Our work deepens the comprehension of covered target imaging. Benefited fields might include non-destructive testing, through-wall imaging, subsurface imaging, and security screening.

Passive polarimetric imaging of millimeter and terahertz waves for personnel security screening.

Passive millimeter and terahertz wave imaging is a powerful way for personnel security inspection and scene monitoring. The existing systems usually have a single polarization mode. To obtain more information, polarimetric imaging has been preliminarily explored recently. However, there is no work exhibiting high-performance polarimetric imaging to analyze and interpret polarization characteristics. In this Letter, we report on the development of a W-band passive polarimetric imaging system for human body screening and present the polarization characteristics analysis of several typical scenarios. The experimental system has a spatial resolution of better than 2 cm at 2.5 m distance and has a thermal sensitivity of better than 0.3 K. The system can display polarization properties of human bodies and concealed objects. The experimental results demonstrate that passive polarimetric imaging has a great potential for object contrast enhancement, detection, segmentation, and recognition.

Concealed object enhancement using multi-polarization information for passive millimeter and terahertz wave security screening.

Passive millimeter and terahertz wave imaging has become a significant potential technique for human security check and scene monitoring. Due to the small difference of the brightness temperatures between human body and concealed objects, the temperature sensitivity and spatial resolution of radiometers are always the key performance indexes which are difficult to improve. Therefore, when the hardware performance is given, improving detectivity becomes a pressing need. In this paper, a physically-based concealed object enhancement method using multi-polarization information is presented. The polarization model and polarization property of human body and concealed objects have been analyzed. By fusing multiple polarization images, we can obtain a complete polarization image in which the contrast between human body and concealed objects is enhanced and stable. The experimental results of simulation and measurement demonstrate the enhancement performance, and Differential Signal Noise Ratio (DSNR) is obviously improved by using the proposed method.

Three-Dimensional Graphene Field-Effect Transistors as High-Performance Photodetectors.

Graphene is an ideal material for high-performance photodetectors because of its superior electronic and optical properties. However, graphene's weak optical absorption limits the photoresponsivity of conventional photodetectors based on planar (two-dimensional or 2D) back-gated graphene field-effect transistors (GFETs). Here, we report a self-rolled-up method to turn 2D buried-gate GFETs into three-dimensional (3D) tubular GFETs. Because the optical field inside the tubular resonant microcavity is enhanced and the light-graphene interaction area is increased, the photoresponsivity of the resulting 3D GFETs is significantly improved. The 3D GFET photodetectors demonstrated room-temperature photodetection at ultraviolet, visible, mid-infrared, and terahertz (THz) regions, with both ultraviolet and visible photoresponsivities of more than 1 A W-1 and photoresponsivity of 0.232 A W-1 at 3.11 THz. The electrical bandwidth of these devices exceeds 1 MHz. This combination of high photoresponsivity, a broad spectral range, and high speed will lead to new opportunities for 3D graphene optoelectronic devices and systems.

C-curve feature of complex permittivity estimation based on multi-polarization measurements in passive millimeter-wave sensing.

Passive millimeter-wave (PMMW) sensing has been used for several close-range applications such as scene monitoring and security check. Aiming to sense man-made or natural dielectrics, we report the estimation characteristics of complex permittivity by multi-polarization measurements. According to the polarization brightness temperature (TB) model, the complex permittivities of dielectric materials are estimated by using the TB data of multiple linear polarizations. By Monte Carlo simulations, we found that the estimated complex permittivities can form a special cluster. All estimation values of each dielectric spread around a special nonlinear curve (called the "C-curve"). Then the "C-curve" distribution characteristics of different parameter conditions such as polarization number, incident angle, roughness, and measurement noise, have been analyzed. The 94 GHz multi-polarization measurements have been conducted to prove the existence of "C-curve" feature. The results suggest that this invariant feature can be possibly used for material classification and image segmentation in PMMW sensing.

Surface-roughness measurement based on scalar field correlation with active millimeter-wave imaging system.

Active millimeter-wave (MMW) imaging is of interest because it has played an important role in the area of personnel surveillance over the past decades. Through reconstructing reflectivity, potential threats can be recognized based on shape. Besides reflectivity, diverse physical characteristics should be explored so that supplementary information can be used to assist recognition. This paper presents a surface-roughness measurement method using holographic data that has already been acquired during security checks. Based on scalar diffraction theory and speckle metrology, a simple mathematical relation between the correlation of holographic fields and surface roughness has been derived. Consequently, another kind of information, that is, the surface-roughness estimate, can be used to help differentiate similarly shaped articles. Results of simulations and laboratory experiments have shown its validation and potential in application to MMW imaging systems.

mTOR up-regulation of BEX4 promotes lung adenocarcinoma cell proliferation by potentiating OCT4.

Previously, BEX family members have been reported to participate in cancer development. However, little is known about the role of BEX4 in lung adenocarcinoma (LAC). Here, we found that BEX4 was over-expressed in LAC tissues compared with adjacent tissues. LAC tissues from metastatic patients exhibited higher expression of BEX4 comparing to those from non-metastatic ones. In vitro, BEX4 ectopic expression accelerated the proliferation of both A549 and H1975 cells. By contrast, knockdown of BEX4 suppressed the proliferation of A549 and H1975 cells. BEX4 positively regulated the expression of OCT4, silencing of which reduced the proliferation of A549 and H1975 cells with over-expressed BEX4. Additionally, mTOR activation, which is frequently observed in LAC, potentiated BEX4 depending on mTORC1 but not mTORC2. BEX4 abundance dictated the sensitivity of A549 and H1975 cells to rapamycin treatment. Our findings reveal that BEX4 is an oncogene in LAC and may contribute to the hyper-active mTOR-induced LAC development.

A Breakthrough Efficiency of 19.9% Obtained in Inverted Perovskite Solar Cells by Using an Efficient Trap State Passivator Cu(thiourea)I.

It is extremely significant to study the trap state passivation and minimize the trap states of perovskite to achieve high-performance perovskite solar cells (PSCs). Here, we have first revealed and demonstrated that a novel p-type conductor Cu(thiourea)I [Cu(Tu)I] incorporated in perovskite layer can effectively passivate the trap states of perovskite via interacting with the under-coordinated metal cations and halide anions at the perovskite crystal surface. The trap state energy level of perovskite can be shallowed from 0.35-0.45 eV to 0.25-0.35 eV. In addition, the incorporated Cu(Tu)I can participate in constructing the p-i bulk heterojunctions with perovskite, leading to an increase of the depletion width from 126 to 265 nm, which is advantageous for accelerating hole transport and reducing charge carrier recombination. For these two synergistic effects, Cu(Tu)I can play a much better role than that of the traditional p-type conductor CuI, probably due to its identical valence band maximum with that of perovskite, which enables to not only lower the trap state energy level to a greater extent but also eliminate the potential wells for holes at the p-i heterojunctions. After optimization, a breakthrough efficiency of 19.9% has been obtained in the inverted PSCs with Cu(Tu)I as the trap state passivator of perovskite.

Terahertz photodetector based on double-walled carbon nanotube macrobundle-metal contacts.

We report on the characterization of a terahertz (THz) photodetector with an extremely simple structure consisting of only a macroscopic bundle of double-walled carbon nanotubes (DWCNTs) suspended between two metal electrodes. Polarization-sensitive, broadband, and significant photoresponse occurring at the DWCNT-metal contacts under THz illumination are observed with room-temperature photocurrent and photovoltage responsivities up to ∼16 mA/W and ∼0.2 V/W at 2.52 THz, respectively. Scanning photocurrent measurements provide evidence that the photothermoelectric mechanism dominates the detector response. The simple geometry and compact nature of our device make it suitable for integration and show promising applications for THz detection.

Compressive sensing for direct millimeter-wave holographic imaging.

Direct millimeter-wave (MMW) holographic imaging, which provides both the amplitude and phase information by using the heterodyne mixing technique, is considered a powerful tool for personnel security surveillance. However, MWW imaging systems usually suffer from the problem of high cost or relatively long data acquisition periods for array or single-pixel systems. In this paper, compressive sensing (CS), which aims at sparse sampling, is extended to direct MMW holographic imaging for reducing the number of antenna units or the data acquisition time. First, following the scalar diffraction theory, an exact derivation of the direct MMW holographic reconstruction is presented. Then, CS reconstruction strategies for complex-valued MMW images are introduced based on the derived reconstruction formula. To pursue the applicability for near-field MMW imaging and more complicated imaging targets, three sparsity bases, including total variance, wavelet, and curvelet, are evaluated for the CS reconstruction of MMW images. We also discuss different sampling patterns for single-pixel, linear array and two-dimensional array MMW imaging systems. Both simulations and experiments demonstrate the feasibility of recovering MMW images from measurements at 1/2 or even 1/4 of the Nyquist rate.

Photocurrent response of carbon nanotube-metal heterojunctions in the terahertz range.

We investigate the optoelectronic properties of a carbon nanotube (CNT)-metal heterostructure in the terahertz range. On the basis of terahertz time-domain spectroscopy characterization of a double-walled CNT (DWNT) film, we present and analyze the photocurrent measurement for a DWNT-nickel heterojunction illuminated by continuous-wave terahertz radiation. A significant current across the junction directly induced by terahertz excitation is observed and a negative photoconductivity behavior is found to occur in the device. The photocurrent shows a linear response to the bias voltage and the illumination power within the examined range. These phenomena support the feasibility of using CNT-metal heterojunctions as novel terahertz detectors.

Assessing the global burden of mesothelioma: trends, socioeconomic influences, and asbestos exposure: a retrospective cohort study.

INTRODUCTION: Mesothelioma is an uncommon type of cancer which has received little attention. This study aims to evaluate the global disease burden; trends of mesothelioma by age, sex, and geographic locations; and its risk factors on the population level. METHODS: The Global Cancer Observatory in 2022 and 2019 Global Burden of Disease were accessed for mesothelioma incidence and its risk factors worldwide. Multivariable linear regression analyses was conducted to explore the associations between mesothelioma incidence and key predictors including Human Development Index (HDI), Gross Domestic Product (GDP) per capita, and occupational asbestos exposure, adjusting for age and sex across global regions. RESULTS: This study identified 30,870 global cases of mesothelioma in 2022, with a higher age-standardized incidence rate (ASR) in males (0.25 per 100,000) compared to females (0.39 per 100,000). Geographical analysis indicated the highest disease burden in Northern Europe, with particular prevalence in more developed regions. The incidence was also significantly associated with higher Human Development Index (HDI), with a beta coefficient of 0.133 overall, and Gross Domestic Product (GDP) per capita, with a beta coefficient of 0.101. These socioeconomic factors exhibited stronger associations in the elderly population, especially with HDI (ß=0.512) and GDP (ß=0.389), than in adults. Additionally, occupational exposure to asbestos remained a significant risk factor across all groups, except for the younger adult population, with an overall beta of 0.122 for incidence. The temporal trend analysis revealed a general decrease in mesothelioma incidence, particularly in the 15-49 years age group. CONCLUSIONS: The analysis indicates a higher mesothelioma incidence in males and in developed regions, with marked disparities noted particularly in Northern Europe. Significant correlations with socioeconomic indicators-HDI and GDP-and occupational asbestos exposure were identified, particularly affecting the elderly. Despite a decline in global incidence, especially among younger individuals, persistent cases in females highlight the need for continued public health measures addressing both occupational and environmental exposures.

Impact of lymph node dissection on cancer-specific survival in non-small cell lung cancer patients: a SEER database analysis.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide, and lymph node dissection (LND) is a significant surgical procedure employed in its management. Although some studies suggest benefits of LND, the extent of its impact on survival, the optimal range of lymph nodes to be examined, and the specific patient groups that benefit most remain areas of active debate and investigation. Methods: A population-based analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed with NSCLC between 2004 and 2017, undergoing primary tumor resection, were included. Descriptive, univariate, and multivariate analyses assessed the effect of LND on survival, and a restricted cubic spline method determined the optimal range for lymph node examination. Results: This study of 37,323 NSCLC patients delved into the impact of LND on lung cancer-specific survival. Key findings revealed a median survival of 19.58 months, with 85% mortality. Baseline characteristics included a majority of White patients (81%), distant stage diagnoses (63%), and 64% with Grade IV tumors. LND emerged as a crucial predictor, influencing survival across age, gender, race, and tumor characteristics. Univariate analysis highlighted its significance, with higher T, N, and M categories, advanced stage, and poorer grade associating with elevated hazard ratios. Multivariate Cox proportional hazards (PH) analysis reinforced LND's impact, showcasing lower hazard ratios post-removal. Hazard ratios for biopsy/aspiration and removal of regional lymph nodes were 0.85 [95% confidence interval (CI): 0.81-0.89; P<0.001] and 0.43 (95% CI: 0.39-0.46; P<0.001), underscoring the protective effect. Visualizations and a U-shaped curve analysis identified an optimal range (24-32 nodes) for examination, emphasizing the nuanced benefits across NSCLC stages. Conclusions: The study findings suggest that LND plays a critical role in improving cancer-specific survival in NSCLC patients, particularly when tailored to the early stages of the disease. The optimal range of lymph nodes examined, between 24 and 32, offers crucial insights for personalized NSCLC treatment strategies and may enhance overall survival. These results underscore the need for refined surgical guidelines that incorporate the extent of LND, supporting the utility of a more personalized approach in NSCLC management.

FAM122A ensures cell cycle interphase progression and checkpoint control by inhibiting B55α/PP2A through helical motifs.

The Ser/Thr protein phosphatase 2 A (PP2A) regulates the dephosphorylation of many phosphoproteins. Substrate recognition are mediated by B regulatory subunits. Here, we report the identification of a substrate conserved motif [RK]-V-x-x-[VI]-R in FAM122A, an inhibitor of B55α/PP2A. This motif is necessary for FAM122A binding to B55α, and computational structure prediction suggests the motif, which is helical, blocks substrate docking to the same site. In this model, FAM122A also spatially constrains substrate access by occluding the catalytic subunit. Consistently, FAM122A functions as a competitive inhibitor as it prevents substrate binding and dephosphorylation of CDK substrates by B55α/PP2A in cell lysates. FAM122A deficiency in human cell lines reduces the proliferation rate, cell cycle progression, and hinders G1/S and intra-S phase cell cycle checkpoints. FAM122A-KO in HEK293 cells attenuates CHK1 and CHK2 activation in response to replication stress. Overall, these data strongly suggest that FAM122A is a short helical motif (SHeM)-dependent, substrate-competitive inhibitor of B55α/PP2A that suppresses multiple functions of B55α in the DNA damage response and in timely progression through the cell cycle interphase.

Specific organ metastases and prognosis in lung adenocarcinoma.

OBJECTIVES: This study aims to characterize the specific organ metastatic rates in lung adenocarcinoma (LUAD) patients and identify the prognosis-associated factors. METHODS: Using the Surveillance, Epidemiology and End Results database, 40 117 patients diagnosed with positive histology as the only primary LUAD were included. We stratified patients by diagnosed year, age, sex, race/ethnicity, marital status, insurance, location, TNM stage, organ-specific metastases, surgery, chemotherapy, and radiation therapy. We performed multivariable logistic and Cox regression to identify the factors associated with the presence of specific organ metastases and prognosis predictors. RESULTS: For the 40 117 LUAD patients, 43.69%, 26.25%, 19.66%, 10.60%, and 17.89% had specific organ, bone, brain, liver, and lung metastases, respectively. The average survival in patients with organ metastases was 12.19 months, compared to 36.40 months in patients without metastases. In different kinds of metastatic organ cohorts, the longest average survival was 12.60 months in the lung metastases cohort, and the shortest was 8.43 months in liver metastases cohort. In total, 571 patients with metastases received surgery, which was significantly associated with decreased mortality (hazard ratio 1.82, 95% confidence interval 1.65-2.01, p < 0.01). Patients received surgery of lobectomy or extended (251 of 571, 43.96%) displayed the longest average survival (35.16 months); patients (294 of 571, 51.49%) received sub-lobar resection, had the average survival (19.90 months); patients received local tumor destruction (26 of 571, 4.55%) had the shortest average survival (13.73 months). CONCLUSION: This study provides insights into the specific organ metastatic rates and prognosis in LUAD patients on a population level. These findings suggest that surgery resection should be taken into consideration in the treatment for these LUAD patients.

Challenges and opportunities of CAR T-cell therapies for CLL.

Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment landscape of blood cancers. These engineered receptors which endow T cells with antibody-like target cell recognition combined with the typical T cell target cell lysis abilities. Introduced into the clinic in the 2010s, CAR T-cells have shown efficacy in chronic B lymphocytic leukemia (CLL), but a majority of patients do not achieve sustained remission. Here we discuss the current treatment landscape in CLL using small molecules and allogeneic stem cell transplantation, the niche CAR T-cells filled in this context, and what we have learned from biomarker and mechanistic studies. Several product parameters and improvements are introduced as examples of how the bedside-to-bench is translated into improved CAR T-cells for CLL. We hope to convey to our readers the crucial role translational medicine plays in transforming the treatment outcomes for patients with CLL and how this line of research is an essential component of modern medicine.

Prognostic significance of eighth edition TNM stage criteria in combined small-cell lung cancer.

Objectives: This study aimed to evaluate the prognostic significance of the eighth edition TNM stage criteria in patients with combined small-cell lung cancer (C-SCLC) on a population level. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with C-SCLC (histology code 8245) between the years 2004 and 2015 were identified. We performed a Kaplan-Meier analysis and used the multivariable cox regression proportional hazards model to obtain prognostic overall survival estimates for each group of patients. Results: A total of 477 patients diagnosed with C-SCLC were identified. The T, N, M, TNM, and combined TNM stage status of the eighth edition were all significant prognostic factors for patients' overall survivals, with the best discrimination identified in the combined stages. Surgery was also found to be a prognostic factor (HR =1.95, 95%CI =1.49-2.56, p<0.01) for patients with C-SCLC. Conclusions: The combined eighth edition of the TNM staging criteria shows reliable prognostic significance in patients with C-SCLC. Moreover, surgery might be significant for improving the patients' prognosis.