Objective Of Phase Research Articles

Differentiable pixel-super-resolution lensless imaging

Conventional lensless imaging systems require complex phase diversity measurements and sequential processing steps, limiting their practical application despite their compact design. We present a differentiable end-to-end pixel-super-resolution (dPSR) technique that unifies PSR hologram synthesis, autofocusing, and complex-field reconstruction within a single optimization framework. By jointly optimizing these traditionally separate processes, our method eliminates both phase diversity requirements and error accumulation from sequential processing. Our method achieves superior position estimation accuracy (mean error 0.0282 pixels versus 0.1172 pixels with conventional methods), delivering precise autofocusing with accuracy better than 0.3 µm, and enabling a twofold resolution enhancement beyond the sensor’s native pixel size. This robust performance is validated through both simulated and experimental results, including challenging phase objects and label-free cell imaging, establishing dPSR as a practical solution for high-resolution microscopy applications.

Safety, tolerability, and preliminary efficacy of tinodasertib as a monotherapy or in combination with pembrolizumab or irinotecan in metastatic colorectal cancer: Interim results from a phase II open-label, dose-finding, run-in and cohort expansion study.

183 Background: MNK inhibition has been shown to downregulate phosphorylation at serine 209 of eIF4E, a potent regulatory point of CAP-mediated translation of 5’ polyadenylated mRNA associated with growth factor and pro-oncogenic signals in cells. Elevated levels of eIF4E phosphorylation are observed in a broad range of tumors. MNK1/2 knock out mice are healthy and viable, as cellular house-keeping mRNA translation occurs readily using the IRES mechanism, whereas mRNA with more complex and longer 5’ untranslated ends such as those involved in growth factor and pro-oncogenic signaling, are MNK activated. Cells from MNK knockout animals become relatively resistant to subsequent oncogenic transformation. In a program of SAD and MAD Phase I studies conducted in normal healthy volunteers, Tinodasertib was found to be safe and well tolerated with no dose-limiting toxicity (DLT). The objectives of this ongoing Phase 2 study are to evaluate safety, and preliminary efficacy of Tinodasertib as monotherapy and in combination with either pembrolizumab or irinotecan in patients with advanced colorectal cancer (CRC). Methods: Patients had to have advanced CRC and previously received ≥2 lines of therapy. The dose escalation phase of the study was open to all patients with CRC. As of 23 July 2024, 22 patients were dosed in a modified 3X3 dose escalation design with Tinodasertib from 20 to 80 mg on alternate days. Out of 22 patients, 12 received monotherapy, 4 were treated with Tinodasertib and Irinotecan and 6 were treated with Tinodasertib and pembrolizumab. Majority (19) had MSS CRC and 3 had unknown status. Nine patients had KRAS-mut CRC. Results: No DLTs were observed and MTD was not reached. Grade 3 treatment-related adverse events (TRAEs) were observed in 2 (9%) patients and were related to irinotecan while no Grade 3 AEs were attributed to Tinodasertib by either the investigator or the sponsor. Most common TRAEs were related to gastrointestinal system organ class. There were no Grade 4-5 TRAEs. Of the 22 patients, 18 were evaluable for RECIST 1.1 response. No patient had an objective response to treatment, 12 had stable disease with disease control rate of 67% and a progression free survival of 2.99 months. Patients remained on therapy for up to 28 weeks. Overall survival (OS) at 52 weeks was 52% (CI 29 to 93). Conclusions: Tinodasertib either as monotherapy or combined with irinotecan or pembrolizumab, was well tolerated with no DLTs at the dose levels evaluated. Prolonged median time to progression and OS compared to historical controls were observed even during the dose escalation phase for the study population as a whole and for each of the monotherapy and combination arms. Enrolment in the dose escalation phase continues. Clinical trial information: NCT05462236 .

EVEREST-2: A seamless phase 1/2 study of A2B694, a logic-gated Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with pancreatic cancer (PANC) or other mesothelin (MSLN)-expressing solid tumors and human leukocyte antigen (HLA)–A*02 loss of heterozygosity (LOH).

TPS788 Background: MSLN is a desirable candidate for targeted therapy given its limited expression in normal tissues and its overexpression in several malignancies, including PANC, mesothelioma, non-small cell lung, and ovarian cancers (TCGA 2022). MSLN-targeted CAR T and T-cell receptor therapies have shown promising clinical activity; however, on-target, off-tumor toxicity, including fatal events, have occurred (1-3). Autologous logic-gated Tmod CAR T therapies address the challenges of on-target, off-tumor toxicity by combining 2 CARs: activating and blocking receptors. The activator recognizes a tumor-associated antigen present on the surface of both tumor and normal cells; the blocker prevents CAR T activity when it binds HLA-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells due to retained HLA-A*02 expression (4). HLA-A*02 LOH is observed in various solid tumors, including ~20% of PANC (5). Two autologous CAR T therapies are currently under investigation: A2B530, targeting carcinoembryonic antigen, in the EVEREST-1 trial, and A2B694, targeting MSLN, in the EVEREST-2 trial, described herein. A2B694 may provide a therapeutic window to treat patients with PANC and other MSLN-expressing solid tumors exhibiting HLA-A*02 LOH due to its unique discriminatory mechanism. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 for recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including PANC. Eligible patients must have exhausted options of potentially curative therapy and have recurrent disease. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), in which patients with tumor-associated HLA-A*02 LOH are identified via next-generation sequencing (Tempus AI, Inc) and leukapheresis product is collected. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess the primary endpoint overall response rate per RECIST v1.1 and secondary endpoints progression-free survival and overall survival. The first patient was dosed on April 24, 2024 and dose escalation is ongoing. 1. Beatty, et al. Gastroenterology . 2018. 2. Haas, et al. Mol Ther . 2023. 3. Hong, et al. ESMO 2021. Abstr 9590. 4. Hamburger, et al. Mol Immunol . 2020. 5. Hecht, et al. J Clin Oncol . 2022. Clinical trial information: NCT06051695 .

Phase contrast ghost imaging using pseudo-thermal light

Ghost imaging and ghost holography enable non-local imaging of amplitude and phase objects. Recent studies have indicated that dual-arm phase-contrast imaging can be achieved by extracting only the edges of the target, thereby obviating the need for a full image reconstruction. However, existing approaches still depend on either cameras or complex scanning procedures. In this paper, we combine spiral phase contrast imaging with ghost imaging and propose a computational dual-arm phase contrast imaging scheme based on Fourier basis modulation under speckle illumination, with single-point detection used in both arms. Experimental and simulation results validate the feasibility of the proposed scheme and demonstrate its effective implementation under compressed sampling. Furthermore, we also experimentally investigate the impact of the lateral coherence length of the speckle on edge extraction accuracy, as well as the effect of the number of speckles on the imaging signal-to-noise ratio.

First-in-Human Phase 1 study of a CD16A bispecific innate cell engager, AFM24, targeting EGFR-expressing solid tumors.

Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on natural killer (NK) cells/macrophages and EGFR on tumor cells, redirecting antitumor activity towards tumors. The safety and tolerability of AFM24 was evaluated in this Phase 1/2a dose escalation/dose expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR. The main objective in Phase 1 was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the observation period. Secondary endpoints included the incidence of treatment emergent adverse events and pharmacokinetics. In the dose escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14-720 mg). One patient experienced a DLT of Grade 3 infusion-related reaction (IRR). IRRs were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics were dose-proportional and CD16A receptor occupancy on NK cells approached saturation between 320-480 mg. Paired tumor biopsies demonstrated activation of innate and adaptive immune responses within the tumor. Best objective response was stable disease in 10/35 patients; four had stable disease for 4.3-7.1 months. AFM24 was well tolerated with 480 mg established as the RP2D. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.

Advanced Quantitative Phase Microscopy Achieved with Spatial Multiplexing and a Metasurface.

Quantitative optical phase information provides an alternative method to observe biomedical properties, where conventional phase imaging fails. Phase retrieval typically requires multiple intensity measurements and iterative computations to ensure uniqueness and robustness against detection noise. To increase the measurement speed, we propose a single-shot quantitative phase imaging method with metasurface optics that can be conveniently integrated into conventional imaging systems with minimal modification. The improvement of the measurement speed is simultaneously made possible by combining deep learning with the transport-of-intensity equation. As a proof-of-concept, we demonstrate phase retrieval on both calibrated phase objects and biological specimens by using an imaging system integrated with our metasurface. When combined with the matched neural network, the system yields result with errors as low as 5% and increased space-bandwidth-product. A multitude of commercial applications can benefit from the compactness and rapid implementation of our proposed method.

Impact of Platelet Transfusion at Different Doses in Oncohematology Pediatric Inpatients and Outpatients: A Retrospective Study.

Platelet (PLT) transfusion is an essential strategy to prevent bleeding in children with thrombocytopenia associated to cancer treatment. However, data on optimal pediatric dosing and transfusion thresholds are limited. This retrospective study analyzed data from 607 pediatric patients with hematologic malignancies, nonmalignant disorders, and solid tumors who developed hypoproliferative thrombocytopenia during therapy. In the first phase (Objective 1), the effective response to transfusion (ERTR) was assessed following International Collaboration for Transfusion Medicine guidelines (ICTMG), comparing low-dose (1.1×1011PLT/m2 body surface area) transfusions for inpatients and medium dose (2.2×1011) for outpatients. Transfusion thresholds were set at less than 10,000/µL versus 10,000-20,000/µL, and overall PLT concentrate consumption was analyzed. The second phase (Objective 2) examined the total number of transfusions per patient, incidence of major bleeding events, and bleeding-related mortality rates across dosing groups. ERTR ranged from 65% to 82%, with significantly higher rates in outpatients compared to inpatients. In outpatients with PLT less than 10,000/µL, the medium dose showed no significant advantage over the lower inpatient dose. Similar efficacy was observed between low (<10,000/µL) and high (10,000-20,000/µL) transfusion triggers, with no statistically significant difference in the incidence of major bleeding events across groups. The low-dose strategy was significantly associated with a reduction in PLT volume transfused compared to the standard expected dose. These findings support the application of ICTMG in pediatric settings. The lower PLT dose for inpatients is safe and effective, providing benefits in resource utilization, while a higher transfusion trigger (20,000/µL) does not improve outcomes.

Retrieval of Phase Information from Low-Dose Electron Microscopy Experiments: Are We at the Limit Yet?

The challenge of imaging low-density objects in an electron microscope without causing beam damage is significant in modern transmission electron microscopy. This is especially true for life science imaging, where the sample, rather than the instrument, still determines the resolution limit. Here, we explore whether we have to accept this or can progress further in this area. To do this, we use numerical simulations to see how much information we can obtain from a weak phase object at different electron doses. Starting from a model with four phase values, we compare Zernike phase contrast with measuring diffracted intensity under multiple random phase illuminations to solve the inverse problem. Our simulations have shown that diffraction-based methods perform better than the Zernike method, as we have found and addressed a normalization issue that, in some other studies, led to an overly optimistic representation of the Zernike setup. We further validated this using more realistic 2D objects and found that random phase illuminated diffraction can be up to five times more efficient than an ideal Zernike implementation. These findings suggest that diffraction-based methods could be a promising approach for imaging beam-sensitive materials and that current low-dose imaging methods are not yet at the quantum limit.

Color-multiplexed 3D differential phase contrast microscopy with optimal annular illumination.

Quantitative phase imaging (QPI) has become a valuable tool in the field of biomedical research due to its ability to quantify refractive index variations of live cells and tissues. For example, three-dimensional differential phase contrast (3D DPC) imaging uses through-focus images captured under different illumination patterns deconvoluted with a computed 3D phase transfer function (PTF) to reconstruct the 3D refractive index. In conventional 3D DPC with semi-circular illumination, partially spatially coherent illumination often diminishes phase contrast, exacerbating inherent noise, and can lead to a large number of zero values in the 3D PTF, resulting in strong low-frequency artifacts and deteriorating imaging resolution. To overcome the above drawbacks, we obtain the conditions for acquiring the optimal 3D PTF based on the analysis of the 3D imaging model and the derivation of the 3D PTF calculation process and propose a 3D DPC microscopy based on optimal annular illumination. The proposed optimal annular illumination pattern minimizes the missing frequency components in the 3D Fourier space, resulting in the best noise-robustness and significantly increased phase contrast. To expedite imaging speed, we utilize a 1/2 annular multiplexed illumination, reducing data acquisition volume by 75%. The 3D refractive index tomography of a simulated 3D phase object, unstained tongue sections, and oral epithelial cells demonstrates that our proposed method achieves the above advantages. In conclusion, we demonstrate a novel 3D DPC microscope that only requires replacing the illumination of a commercial microscope with a programmable LED array. The accurate 3D refractive index tomography and the compactness of the system setup allow the method to play a significant role in the biomedical field.

Combined speckle- and propagation-based single shot two-dimensional phase retrieval method

Single-shot two-dimensional (2D) phase retrieval (PR) can recover the phase shift distribution within an object from a single 2D x-ray phase contrast image (XPCI). Two competing XPCI imaging modalities often used for single-shot 2D PR to recover material properties critical for predictive performance capabilities are: speckle-based (SP-XPCI) and propagation-based (PB-XPCI) XPCI imaging. However, PR from SP-XPCI and PB-XPCI images are, respectively, limited to reconstructing accurately slowly and rapidly varying features due to noise and differences in their contrast mechanisms. Herein, we consider a combined speckle- and propagation-based XPCI (SPB-XPCI) image by introducing a mask to generate a reference pattern and imaging in the near-to-holographic regime to induce intensity modulations in the image. We develop a single-shot 2D PR method for SPB-XPCI images of pure phase objects without imposing restrictions such as object support constraints. It is compared against PR methods inspired by those developed for SP-XPCI and PB-XPCI on simulated and experimental images of a thin glass shell before and during shockwave compression. Reconstructed phase maps show improvements in quantitative scores of root-mean-square error and structural similarity index measure using our proposed method.

Two camera phase contrast imaging using digital correlation imaging of speckles

In this paper, we demonstrate quantitative phase contrast imaging using temporal digital speckle correlation imaging. The system consists of two identical imaging arms, where one of the arms is used as a reference and the other is used to image the phase object under study. The speckled illumination is produced by laser light scattered off a rotating diffuser. The imaging principle is based on the deflection of light in the Fourier plane of an imaging system in the presence of a phase gradient and the decorrelation this causes of a speckle pattern. In the paper, the technique is theoretically described and demonstrated both through simulations and experiments using a dried-out eye contact lens as a phase object.

Accurate fast quantitative phase imaging based on accelerative iterative transport of the intensity equation solution.

As a simple and widely used quantitative phase imaging (QPI) approach, the transport of intensity equation (TIE) is plagued by accuracy and applicability issues due to the limitations of conventional solution algorithms. To address these problems, we present an accurate fast QPI method using an accelerated iteration-based TIE solution. In this method, a gradient acceleration iterative solution is constructed by TIE itself. In this manner, the restrictions in TIE ("phase discrepancy" and "phase singularity" issues) are bypassed, resulting in a fast convergence TIE numerical algorithm with great applicability. In addition, by using high-accurate multi-plane intensity derivative estimation result as initial iteration value, the accuracy and noise robustness of phase reconstruction are significantly improved. Finally, an accurate, fast, and widely applicable QPI can be achieved. Experiments on various phase objects, including phase plates and living cells, demonstrate the accuracy, applicability, and real-time measurement ability of our method. Our method provides a general TIE algorithm for accurate real-time QPI.

Visualization of pure phase objects with optical spatial differentiation operations.

Phase distributions typically contain richer information about the morphology, structure, and organizational properties of a sample than intensity distributions. However, due to the weak scattering and absorption properties of pure phase objects, intensity measurements are unable to provide information about the phase, making it more challenging to reveal phase structure from the incident light background. Here, we propose a method for visualizing phase objects through simple optical reflection occurring at a glass interface. By exploiting the spin-orbit interaction of light and the Brewster effect, it is possible to perform a two-dimensional differentiation operation on the input light field. This enables high-contrast, isotropic differential images for pure phase objects. Experimental measurements are conducted on pure phase masks with different phase jumps to verify the superiority of our method. Additionally, bias retardation is introduced based on the differential system, thereby enabling phase reconstruction of low-contrast phase objects. The proposed mechanism for visualizing pure phase objects may lead to important applications in versatile and high-contrast bioimaging.

First-in-Human Phase I Clinical Trial of the Adenosine A1R/A3R Agonist AST-004 in Healthy Subjects.

AST-004 is a small-molecule adenosine A1/A3 receptor agonist that has exhibited significant cerebroprotective efficacy in preclinical models of acute ischemic stroke and traumatic brain injury. The primary objectives of this clinical phase I first-in-human study were to evaluate the safety and tolerability profile of single ascending intravenous doses in healthy subjects. The secondary objectives were to characterize the single-dose pharmacokinetic profiles in plasma, cerebrospinal fluid (CSF), and urine. In part 1 of the study, AST-004 was administered in ascending dose cohorts of 5, 25, 50, 75, and 100 mg, with 6 subjects in each cohort receiving the study drug and 2 receiving placebo. In part 2, all 12 subjects received a 100 mg IV infusion of the study drug followed by a single CSF collection per subject via lumbar puncture at 20, 40, or 60 minutes after infusion. A total of 42 subjects received AST-004, with no severe or serious adverse events observed. Twelve of these subjects experienced a treatment-emergent adverse event, the most frequent across groups being headache. In part 2, pharmacokinetic analyses confirmed that AST-004 was distributed in the CSF, with the CSF-to-plasma ratio increasing over the 3 timepoints sampled. The mean half-life was 1.1 to 1.4 hours for doses of 25 to 100 mg, and the geometric mean maximum plasma concentration obtained in the highest dosing cohort (100 mg) was 2232±428 ng/mL. AST-004 was safe and well-tolerated at plasma concentrations 3 to 8× higher than those associated with significant efficacy in astrocyte's preclinical primate stroke efficacy studies, with CSF concentrations highest at the 60-minute collection timepoint, the last timepoint tested. This study supports additional clinical investigations, including evaluation of an extended infusion to support the phase 2 program in stroke and traumatic brain injury.

On quantitativeness of diffraction-limited quantitative phase imaging

Quantitative phase imaging (QPI) has advanced by accurately quantifying phase shifts caused by weakly absorbing biological and artificial structures. Despite extensive research, the diffraction limits of QPI have not been established and examined. Hence, it remains unclear whether diffraction-affected QPI provides reliable quantification or merely visualizes phase objects, similar to phase contrast methods. Here, we develop a general diffraction phase imaging theory and show that it is intrinsically connected with Rayleigh’s resolution theory. Our approach reveals the entanglement of phases under restoration, imposing diffraction bounds on spatial phase resolution and, unexpectedly, on phase accuracy. We prove that the phase accuracy depends on the size, shape, and absorption of objects forming the sample and significantly declines if the object size approaches the Rayleigh limit (a relative phase error of −16% for an Airy disk-sized object with low phase shift). We show that the phase accuracy limits can be enhanced at the cost of deteriorated phase resolution by attenuating the sample background light. The QPI diffraction limits are thoroughly examined in experiments with certified phase targets and biological cells. The study’s relevance is underscored by results showing that the phase accuracy of some structures is lost (a relative phase error of −40%) even though they are spatially resolved (a phase visibility of 0.5). A reliable procedure is used to estimate phase errors in given experimental conditions, opening the way to mitigate errors’ impact through data post-processing. Finally, the phase accuracy enhancement in super-resolution QPI is discovered, which has not been previously reported.

Phase Retrieval of One-Dimensional Objects by the Multiple-Plane Gerchberg–Saxton Algorithm Implemented into a Digital Signal Processor

In the current study, we address the phase retrieval of one-dimensional phase objects from near-field diffraction patterns using the multiple-plane Gerchberg–Saxton algorithm, which is still widely used for phase retrieval. The algorithm was implemented in a low-cost digital signal processor capable of fast Fourier transform using Q15 arithmetic, which is used by the previously mentioned algorithm. We demonstrate similarity between one-dimensional phase objects, i.e., vectors cut out of a phase map of the tertiary spherical aberration retrieved by the multiple-plane Gerchberg–Saxton algorithm, and these vectors are measured with a non-contact profiler. The tertiary spherical aberration was induced by a phase plate fabricated using grayscale lithography. After subtracting the vectors retrieved by the algorithm from those measured with the profiler, the root mean square error decreased, while a corresponding increase in the Strehl ratio was observed. A single vector of size 64 pixels was retrieved in about 2 min. The results suggest that digital signal processors that are capable of one-dimensional FFT and fixed-point arithmetic in Q15 format can successfully retrieve the phase of one-dimensional objects, and they can be used for applications that do not require real-time operation, i.e., analyzing the quality of cylindrical micro-optics.

Divergence and Similarity Characteristics for Two Fuzzy Measures Based on Associated Probabilities

Abstract: The article deals with the definitions of the distance, divergence, and similarity characteristics between two finite fuzzy measures, which are generalizations of the same definitions between two finite probability distributions. As is known, a fuzzy measure can be uniquely represented by the so-called its associated probability class (APC). The idea of generalization is that new definitions of distance, divergence, and similarity between fuzzy measures are reduced to the definitions of distance, divergence, and similarity between the APCs of fuzzy measures. These definitions are based on the concept of distance generator. The proof of the correctness of generalizations is provided. Constructed distance, similarity, and divergence relations can be used in such applied problems as: determining the difference between Dempster-Shafer belief structures; Constructions of collaborative filtering similarity relations; non-additive and interactive parameters of machine learning in phase space metrics definition, object clustering, classification and other tasks. In this work, a new concept is used in the fuzzy measure identification problem for a certain multi-attribute decision-making (MADM) environment. For this, a conditional optimization problem with one objective function representing the distance, divergence or similarity index is formulated. Numerical examples are discussed and a comparative analysis of the obtained results is presented.

Wavefront reconstruction of discontinuous phase objects using directional derivatives

Here, we present a model that uses directional derivatives to recover wavefronts from discontinuous data, which leads to minimizing the noise contribution to the reconstruction. This model’s solution yields a nonlinear partial differential equation that is simple to solve using a well-established numerical technique. We give numerical reconstructions that show the potential of the proposed model using both synthetic and experimental data.

Dose-efficient phase-contrast imaging of thick weak phase objects via OBF STEM using a pixelated detector.

Optimum bright-field scanning transmission electron microscopy (OBF STEM) is a recently developed low-dose imaging technique that uses a segmented or pixelated detector. While we previously reported that OBF STEM with a segmented detector has a higher efficiency than conventional STEM techniques such as annular bright field (ABF), the imaging efficiency is expected to be further improved by using a pixelated detector. In this study, we adopted a pixelated detector for the OBF technique and investigated the imaging characteristics. Because OBF imaging is based on the thick weak phase object approximation (tWPOA), a non-zero crystalline sample thickness is considered in addition to the conventional WPOA, where the pixelated OBF method can be regarded as the theoretical extension of single side band (SSB) ptychography. Thus, we compared these two techniques via signal-to-noise ratio transfer functions (SNRTFs), multi-slice image simulations, and experiments, showing how the OBF technique can improve dose efficiency from the conventional WPOA-based ptychographic imaging.

Transport-of-intensity differential phase contrast imaging: defying weak object approximation and matched-illumination condition

Quantitative phase imaging (QPI) has emerged as a promising label-free imaging technique with growing importance in biomedical research, optical metrology, materials science, and other fields. Partially coherent illumination provides resolution twice that of the coherent diffraction limit, along with improved robustness and signal-to-noise ratio, making it an increasingly significant area of study in QPI. Partially coherent QPI, represented by differential phase contrast (DPC), linearizes the phase-to-intensity transfer process under the weak object approximation (WOA). However, the nonlinear errors caused by WOA in DPC can lead to phase underestimation. Additionally, DPC requires strict matching of the illumination numerical aperture (NA) to ensure the complete transmission of low-frequency information. This necessitates precise alignment of the optical system and limits the flexible use of objective and illumination. In this study, the applicability of the WOA under different coherence parameters is explored, and a method to defy WOA by reducing the illumination NA is proposed. The proposed method uses the transport-of-intensity equation through an additional defocused intensity image to recover the lost low-frequency information due to illumination mismatch, without requiring any iterative procedure. This method overcomes the limitations of DPC being unable to recover large phase objects and does not require the strict illumination matching conditions. The accurate quantitative morphological characterization of customized artifact and microlens arrays that do not satisfy WOA under non-matched-illumination conditions demonstrated the precise quantitative capability of the proposed method and its excellent performance in the field of measurement. Meanwhile, the phase retrieval of tongue slices and oral epithelial cells demonstrated its application potential in the biomedical field. The ability to accurately recover phase under a concise and implementable optical setup makes it a promising solution for widespread application in various label-free imaging domains.