Moreover, the high imprinting efficiency (k′ = 9.67) of the AuNP-MIP plasmonic sensor was determined by comparison with the AuNP-NIP plasmonic sensor. All kinetic results were validated and confirmed by HPLC.Herein, gold nanoparticles (AuNP)-modified cortisol-imprinted (AuNP-MIP) plasmonic sensor was developed for signal amplification and real-time cortisol determination in both aqueous and complex solutions. Firstly, the sensor surfaces were modified with 3-(trimethoxylyl)propyl methacrylate and then pre-complex was prepared using the functional monomer N-methacryloyl-L-histidine methyl ester. The monomer solution was made ready for polymerization by adding 2-hydroxyethyl methacrylate to ethylene glycol dimethacrylate. In order to confirm the signal enhancing effect of AuNP, only cortisol-imprinted (MIP) plasmonic sensor was prepared without AuNP. To determine the selectivity efficiency of the imprinting process, the non-imprinted (AuNP-NIP) plasmonic sensor was also prepared without cortisol. The characterization studies of the sensors were performed with atomic force microscopy and contact angle measurements. The kinetic analysis of the AuNP-MIP plasmonic sensor exhibited a high correlation coefficient (R Cortisol is one of the most important glucocorticoids synthesized in the zona fasciculate of the adrenal cortex. It is released in response to physiological stress and has various effects on different functions in the body. It can also affect almost every organ system such as nervous, immune, cardiovascular, respiratory, reproductive, musculoskeletal, and covering systems . FurtherThe conventional clinical assessment of cortisol levels is performed using a variety of test methods, including radioimmunoassays, chromatographic techniques, flow immunoassays, fluorimetric tests, and enzyme-linked immunosorbent tests ,8,9. TodSensors are promising analytical tools that provide a high selectivity and sensitivity and can also be miniaturized and fully automated. They are categorized into three main groups such as optical, electrochemical, and mass . OpticalRecently, the application of noble metal-based nanoparticles (NP) such as gold (Au) and silver (Ag) can increase the sensitivity of sensors due to their ability to enhance responses . AuNP wiHerein, a selective amplification of plasmonic sensor signals for cortisol detection was obtained using gold nanoparticles. After the preparation and characterization steps, kinetic studies were performed with plasmonic sensors. The cortisol samples were prepared at different concentrations and interacted with the plasmonic sensors. Then, the binding kinetic parameters were calculated, and the sensing performance was investigated. In addition, selectivity, reusability, and complex sample analysis spiked with cortisol were performed. Finally, the plasmonic sensor detection ability was validated by HPLC analyses.L-histidine methyl ester and methacryloyl chloride used in the synthesis of N-methacryloyl-L-histidine methyl ester (MAH) monomer. Sodium citrate tribasic dehydrate, gold (III) chloride trihydrate, 3-(trimethoxylyl)propyl methacrylate (TMSPM), 2-hydroxyethyl methacrylate (HEMA), azoisobisbutyronitrile (AIBN), and ethylene glycol dimethacrylate (EGDMA) were obtained from Sigma. Cortisol was purchased from Merck. Plasmonic sensor surfaces were purchased from GenOptics. SPR imager II (GWC Technologies) device was used for sensing. The sensor surfaces had 1 mm × 18 mm × 18 mm of dimensions and 50 nm of gold thickness. The laser light source of the system was Quartz Halogen Lamps (6 volts 10 watts 2000 H). SF10 equilateral prism was used.Synthesis of MAH was carried out by applying a procedure performed formerly . Briefly−1. AuNP was prepared by reduction of HAuCl4 salt to Au using sodium citrate according to the Turkevich method [Fourier transform infrared (FTIR) spectroscopy was used for functional group analysis of MAH, MAH-AuNP, MAH-AuNP-cortisol pre-complexes, and also cortisol. The FTIR spectra of the samples were obtained separately with placing samples at the slot of the device and the total amounts of transmittance were measured in the wavenumber range of 400–4000 cmh method . A dynamh method :(1)N=π6ρA to Avogadro’s number, and V to the solution volume.Equation (1) was used to calculate the number of Au atoms per nanoparticle (N) and Equation (2) was used to calculate AuNP concentration (C). In the equation, M corresponds to the atomic weight of Au, v/v) was added to the chip surface and kept at 35 °C for 24 h. Then, in order to remove the unbound TMSPM monomer, the surface of the plasmonic sensor was washed with ethyl alcohol. For the preparation of the AuNP-MIP plasmonic sensor, firstly the MAH-AuNP complex was formed by coordinating AuNP with the functional monomer. Then, MAH-AuNP complex was mixed with cortisol to prepare the MAH-AuNP-cortisol pre-complex. For this step, 0.4 mmol of MAH monomer was incubated with 0.01 nmol of AuNP in a rotator at 20 rpm for 1 h. Then, 0.05 mmol of cortisol was mixed with the MAH-AuNP complex on a rotator at 20 rpm for 1 h to form the MAH-AuNP-cortisol pre-complex as seen in v/v, 1:1). For this purpose, the plasmonic sensor was washed in 20 mL of desorption solution in a shaking incubator at 90 rpm and room temperature for 2 h. Afterwards, the desorbed sensor surface was washed in a mixture of deionized water and ethyl alcohol and dried in an oven (40 °C). MIP plasmonic sensor was fabricated by the procedure used for the preparation of the AuNP-MIP plasmonic sensor without the addition of AuNP. Besides, AuNP-NIP plasmonic sensor was prepared by the procedure used for the preparation of the AuNP-MIP plasmonic sensor except for the addition of cortisol.The modification step was performed by direct attachment of vinyl group onto gold chip surface as shown in 2. In order to determine the hydrophilicity of AuNP-MIP, MIP, and AuNP-NIP plasmonic sensor surfaces, contact angle values measuring wettability were determined by KRUSS DSA100 device. During the process, the contact angle values were obtained by the sessile drop method and the wettability was measured by dropping of water on the surfaces. After dropping water to three different regions, images were taken in each region and different contact angles were determined. FTIR spectroscopy was used for the analysis of functional groups of AuNP-MIP, MIP, and AuNP-NIP plasmonic sensors. The FTIR spectra of the plasmonic sensors were obtained separately with placing samples at the slot of the device and the total amount of transmittance were measured in the wavenumber range of 400–4000 cm−1.The roughness and depth characterization of bare, AuNP-MIP, MIP, and AuNP-NIP plasmonic sensor surfaces were investigated by atomic force microscopy (AFM) analyses. Asylum Research 3D Standalone device was used to measure the needle tip, which was thinned down to atomic dimensions and sharpened. Two and three-dimensional images were obtained by scanning the surface of the plasmonic sensors with high resolution. The images of the surfaces were taken in half-touch mode by placing them in a diameter with millimeter dimensions in air. While the scanning speed of the images was 1 μm/s, an image was obtained from an area of 1 × 1 μmv/v) was used as an equilibrium solution. After setting an optimum resonance angle, the determined refraction angle was settled as the working angle. SPR view software was used for the kinetic analyses. After the resonance angle was determined, the analyses were carried out by following the equilibrium-adsorption-desorption steps for each concentration. The equilibrium solution was first passed through the sensor system and adjusted to the resonance angle for 180 s. After the system reached equilibrium, cortisol solutions were applied to the sensor system through a peristaltic pump at a flow rate of 0.2 mL/min for 300 s, respectively. The observed shift values in the resonance frequency were reported instantaneously. After observing the change in angle, desorption solution was applied to the system for 120 s. Following the completion of the analysis, the deionized water passed to the system for 10 min and the system was brought to equilibrium solution. These processes were also repeated for each sample applications.SPR imager II device was used to display the surface plasmon curves obtained as a result of kinetic analyses of AuNP-MIP, MIP, and AuNP-NIP plasmonic sensors. When the flow of solution containing cortisol began, the polarized light reached the surface of the plasmonic sensors and the angle of reflected light of the plasmonic sensors was changed during image acquisition in order to determine the %change of refractive index (ΔR) of the light. The ΔR values obtained against the incidence angle of the light for each sample were plotted and reported. Kinetic analyses on samples at different cortisol concentrations were made using SPR device. Firstly, cortisol-containing samples were prepared in the range of 0.01–100 ppb and applied to AuNP-MIP plasmonic sensor. PBS-ethyl alcohol solution  and clobetasol (100 ppb) in the adsorption solution. Equilibrium-adsorption-desorption cycles followed in the competitive analyses were carried out in the same way. In order to determine the imprinting efficiency of the AuNP-MIP plasmonic sensor and the effects of AuNP on the signal response, the MIP and AuNP-NIP plasmonic sensors were fabricated and cortisol solutions (100 ppb) applied to each plasmonic sensors. The selectivity (k) and relative selectivity (k′) coefficients were calculated according to Equations (3) and (4).In order to estimate the reusability of the AuNP-MIP plasmonic sensor, a 100 ppb cortisol sample was prepared in the equilibrium solution and interacted with the sensor in five repetitions. Firstly, adsorption solution was applied to the system for 180 s and the system was brought to the equilibrium. Then, cortisol sample and desorption solution were given to the system one after the other at every 180 s interval. The real-time signal response was observed by performing five repeats of the steps including these processes.In order to evaluate whether AuNP-MIP plasmonic sensor could be used in complex environment or not, artificial plasma and artificial urine samples were prepared and applied to the sensor system. For this purpose, the artificial plasma and artificial urine samples were prepared by spiking cortisol samples at a concentration of 100 ppb in the equilibrium solution and interacted with the AuNP-MIP plasmonic sensor.v/v) as a buffer solution. Prepared buffer solutions were used as mobile phase in HPLC system. Cortisol samples were prepared with artificial plasma and artificial urine at a concentration of 100 ppb. Analyses of the prepared samples were carried out at a wavelength of 220 nm using a C18 column [The detection of the cortisol in the samples applied to the AuNP-MIP plasmonic sensor was confirmed using the HPLC system . Cortisol sample solutions of 1–100 ppb were used to create the calibration curve. While preparing the solutions, they were prepared from stock cortisol solution at a concentration of 1 mg/mL in 10 mM methyl alcohol:acetonitrile:water  for the low concentration range (0.01–1 ppb) was lower than the regression coefficient value (R2 = 0.9857) obtained for the higher concentration range (10–100 ppb) of cortisol. The recorded regression coefficient values confirmed that the AuNP-MIP plasmonic sensor had a higher affinity for the high concentration levels of cortisol, but in total for the whole concentration range, the obtained R2 value was sufficiently higher to explain the behavior of sensor responses. The limit of detection (LOD) and limit of quantity (LOQ) values of AuNP-MIP plasmonic sensor were calculated as 0.0082 ppb and 0.027 ppb, respectively.In this study, AuNP-MIP, MIP, and AuNP-NIP plasmonic sensors were prepared and sensorgrams were obtained as a result of kinetic analyses. The equilibrium solution was passed first, then the adsorption and desorption solutions were passed through the sensor system, and these steps were repeated for each concentration. For real-time cortisol determination with AuNP-MIP plasmonic sensor, kinetic analyses were performed using cortisol samples prepared in the concentration range of 0.01–100 ppb. The sensorgrams of the sensor responses given by AuNP-MIP plasmonic sensor of cortisol solutions prepared at different concentrations were shown in max value (6.991) calculated in the Scatchard analysis was quite close to the experimentally obtained ΔRmax value (7.270). Likewise, according to the binding analysis result, it was observed that cortisol binds to the AuNP-MIP plasmonic sensor surface with an accuracy of 98%  calculated in the Langmuir adsorption isotherm model with the obtained constants was quite close to the experimentally obtained ΔRmax value (7.270). In addition, when the correlation coefficients obtained according to the mathematical calculations were compared, it was seen that the Langmuir adsorption isotherm model (R2 = 0.9999) had a higher correlation coefficient than the Freundlich adsorption isotherm model (R2 = 0.9082). The kinetic constants are summarized in From the kinetic analyses of different cortisol concentrations of AuNP-MIP plasmonic sensor, mathematical calculations were obtained to estimate the best-fitted isotherm model. Two different isotherm models (Langmuir and Freundlich) were applied to determine the type of interaction between the AuNP-MIP plasmonic sensor and the cortisol sample solution. Association and binding kinetic analyses were also obtained. According to the results, the theoretical ΔRy of 98% . FurtherWithin the scope of this study, a sensitive and selective plasmonic sensor was prepared for real-time cortisol determination at a low cost. For this purpose, AuNP was coordinated with MAH containing the amino acid histidine used as the imidazole group provider. The amino acid-based reusable AuNP-MIP plasmonic sensor could detect the cortisol at the ppb concentration level. Molecularly imprinted polymers are used to create a specific cavity and selective recognition sites for the template molecule in a polymeric structure. As shown in In addition, the imprinting efficiency of AuNP-MIP plasmonic sensor was demonstrated with AuNP-NIP plasmonic sensor prepared without using cortisol. It was observed that the ΔR value decreased from 29.52 to 2.73 in the cortisol determination with the 100 ppb concentration made with AuNP-NIP plasmonic sensor B. Thus, Moreover, the selectivity and signal enhancement performances of AuNP-MIP, MIP, and AuNP-NIP plasmonic sensors were obtained by interacting clobetasol (100 ppb) and fluticasone (100 ppb) samples and observed that the interactions of AuNP-NIP and MIP plasmonic sensors were less than the AuNP-MIP plasmonic sensor A. In parThe reusability study of the AuNP-MIP plasmonic sensor was investigated by applying five repetitive equilibrium adsorption-desorption cycles of 100 ppb cortisol solution to the sensor system, and the sensor response was shown in In order to evaluate the AuNP-MIP plasmonic sensor for use in real samples, artificial plasma and artificial urine samples were prepared. As demonstrated in The determination of the cortisol is very important for the human body. Many types of sensors have been developed for the determination of cortisol. Some of the reasons for the increase in studies on sensors in the last two decades are that they have different parameters such as a low detection limit, selectivity, reusability, and can be combined with other methods. In The selective determination of cortisol in artificial plasma and artificial urine samples using AuNP-MIP plasmonic sensor was confirmed with HPLC system. For this purpose, cortisol solutions at concentrations of 1, 25, 50, 75, and 100 ppb were prepared and given to the HPLC system to create a calibration curve . ArtificIn this study, a cortisol-imprinted plasmonic sensor modified with gold nanoparticles was prepared, and then real-time and sensitive cortisol detection was carried out both from an aqueous solution and a complex environment such as artificial plasma and artificial urine without applying any extra complex processes such as ligand immobilization or using any spacer arms. Moreover, the amino acid-based functional monomer containing histidine groups was used as the provider of the complexing agent for AuNP and cortisol molecules in one mode. The AuNP-MIP plasmonic sensor that contained cortisol-specific recognition sites was prepared to detect cortisol selectively, and gold nanoparticles were added to the medium in order to reduce the detection limit of cortisol and increase the sensitivity of the plasmonic sensor signal response. Other advantages of this plasmonic sensor were its thermal and chemical stability, low-cost, long shelf-life, and also more sensitive cortisol detection several times over without extra labeling alternatives to the natural receptors.In a nutshell, different characterization experiments showed that the imprinted polymer was successfully and homogeneously synthesized on the gold surfaces of the plasmonic sensor. Then, kinetic analyses results depicted that the AuNP-MIP plasmonic sensor was able to detect cortisol in real-time with a correlation coefficient of 0.9744 for the 0.01–100 ppb concentration range. Accordingly, the AuNP-MIP plasmonic sensor was found to be 4.96 and 4.71 times more selective to the cortisol than the AuNP-NIP plasmonic sensor for the clobetasol and fluticasone molecules, respectively. The signal enhancement effect was confirmed by evaluating the signal responses of the MIP plasmonic sensor to the cortisol. The signal enhancement factor recorded as 5.6 confirmed the effect of gold nanoparticles on the sensitivity by enhancing the signal response of the plasmonic sensor. Furthermore, it was concluded that the AuNP-MIP plasmonic sensor was able to detect cortisol without any loss of performance in five consecutive reusability analyses. The AuNP-MIP plasmonic sensor could detect cortisol not only in aqueous solutions, but also in complex environments such as artificial plasma and/or artificial urine to evaluate the matrix effect. Validation experiments performed with HPLC studies confirmed the detection ability of the AuNP-MIP plasmonic sensor for the cortisol. At last, it can be concluded that the AuNP-MIP plasmonic sensor as developed is a good proof-of-concept for the future and development of field sensors for use in medical applications.


This imaging modality known as immuno-positron emission tomography (immuno-PET) is currently in fastest-growing and its medical value lies in its ability to give a non-invasive method to assess the in vivo target expression and distribution and provide key-information on the tumor targeting. Currently, immuno-PET presents promising probes for different nuclear medicine topics as staging/stratification tool, theranostic approaches or predictive/prognostic biomarkers. To develop a radiopharmaceutical drug that can be used in immuno-PET approach, it is necessary to find the best compromise between the isotope choice and the immunologic structure . Through some clinical applications, this paper review aims to discuss the most important aspects of the isotope choice and the usable proteic structure that can be used to meet the clinical needs.Radioimmunoconjugates have been used for over 30 years in nuclear medicine applications. In the last few years, advances in cancer biology knowledge have led to the identification of new molecular targets specific to certain patient subgroups. The use of these targets in targeted therapies approaches has allowed the developments of specifically tailored therapeutics for patients. As consequence of the PET-imaging progresses, nuclear medicine has developed powerful imaging tools, based on monoclonal antibodies, to  The original idea of personalized and tailored drugs, highly specific to a pharmacological target, appeared at the beginning of the XXth century via the “magic bullet” concept  brought 131I) radiolabeled mAbs for tumor detection in nuclear medicine practice  in planar or Single Photon Emission Computed Tomography (SPECT) imaging procedures. Despite the reliable and confident clinical information, this modality suffers from several drawbacks including poor sensitivity, poor spatial resolution and complex scatter correction due to the collimator.With the concomitant progress in nuclear medicine, the radiolabeled monoclonal antibody (mAb) quickly emerged to specifically target antigens of abnormal cells, most often cancerous. The discovery of overexpressed antigens in many hematologic and solid tumors paved the way for the use of gamma emitters such as iodine-131 , PET approach seemed unusable with long pharmacokinetic half-life mAbs. The availability in the early 2000s (While Positron Emission Tomography (PET) was revolutionizing diagnostic applications of nuclear medicine with small organic molecules such as fluorodeoxyglucose (FDG) radiolabeled with fluorine-18  allowing antigen targeting in solid tumors, hematological and tumor microenvironment.Today, the overall performance of the immuno-PET methodology is carried by different biological or imaging parameters such target accessibility or imaging protocol . The aim of this paper review is more focused on the pharmacological choices to find the best matching between the radionuclide parameters  and the mAb used . Immuno-PET is a fast-growing approach  in many 2, F(ab), minibody, ScFv, nanobody or affibody structures]. Fluorine-18 and gallium-68 with their shorter half-life may be used to label small molecular weight molecules such as mAb derivates or small synthetic molecules for pretargeting approach . For example, the dosimetry induced by 185 MBq 68Ga-2Rs15d nanobody is close to the dosimetry due to the classical 370 MBq 18F-FDG injection with, respectively, 4 and 7 mSv  derivatives, macrocyclic  –32. ThesFinally, the production way of the isotope has consequences on the cost and in the availability of the radionuclide. The great majority of positron emitters are produced by cyclotron accelerator with a relatively high usual production cost. The half-life of the radionuclide presents a direct impact on the logistic because of decay during the transport. To circumvent this constraint a cyclotron network was built close to nuclear medicine departments for the short half-life isotopes . These particular supply chain leads to a particular production schedule without daily availability of all isotopes. To solve this problem, some isotopes like Gallium-68 can be put in generator form .The discovery of hybridoma technology by Köhler et al.  originalTo adapt these properties (pharmacokinetic and distribution), biochemists and immunochemists have developed some immunoconjugate derivatives exhibit reduced half-lives and improved tumoral penetration. The overall characteristics of these protein structures are summarized on 2 and F(ab). These smaller protein fragments consist in the reduction/digestion of initial mAbs by enzymes (pepsin and papain). The F(ab')2 and F(ab) fragments are smaller  than the native mAbs but preserve the affinity and the specificity for the tumor antigen. F(ab')2 fragments of mAbs were radiolabeled with 64Cu in preclinical studies in breast cancer (68Ga (64Cu (The first improvement was the use of mAbs fragments like F(ab')t cancer  or in lyt cancer  animal mer  or nanobodies. Minibodies consist of constant heavy chain (CH) and variable light (VL) and variable heavy (VH) domains, ScFv constructs are made of solely VL/VH domains and nanobodies has only the VH domains. al model . In breael  generated from a phage display library were produced with a high affinity against an antigenic structure. These proteins, named affibodies, have been prepared against different cancer targets for PET applications and were studied  results –53.in vitro prefunctionalized with a chemical clickable function. The intra-venous injection of this compound is followed by the injection of a radioactive compound with clickable complementary function and a specific covalent bond between these two components is in vivo formed. The relatively short pharmacokinetic half-life of the radioactive clickable moiety allows the use of shorter half-life isotopes and a renewed interest for fluorine-18 in immunoPET applications  for ccRCC. Consolidated results obtained during the REDECT trial (Divgi JCO 2013) showed more robust results with sensitivity and specificity (respectively 86.2 and 85.9%). As consequences, immuno-PET can accurately and non-invasively assess the initial diagnostic of cancer without the inherent risk of biopsies. Despite this promising results, iodine-124 has physics drawbacks and zirconium-89 has been preferred in many subsequent clinical trials with girentuximab .One of the first clinical proof of immuno-PET interest has been reported by Divgi et al.  with a cntuximab , 60. CAIntuximab  or tripl131I or for SPECT imaging with 111In. It is quite natural that it has been used in various immuno-PET studies. For example, AMG211 mAb was a bispecific antibody directed toward CEA and CD3 . M5A mAb is also an anti-CEA mAb and was radiolabeled with 124I for the detection of CEA positive colorectal cancer that has spread to the liver  or with 64Cu for the diagnosis of CEA positive rectal cancer  or in gastrointestinal, lung, medullary thyroid and breast cancers . CEA can also be targeted by a bispecific mAb for a pretargeting approach. TF2 is an engineered bispecific mAb of 157 kDa formed by the Dock-and-Lock® procedure from the anti-hapten Fab fragment recognizing the histamine-succinyl-glycine (HSG) motif and two humanized anti-CEA fragments. During the procedure , non-radioactive TF2 mAb was injected in medullary thyroid carcinoma patients and 24 h later, 68Ga-di-HSG hapten was injected. The preliminary results demonstrated a promising sensitive and specific imaging method (One of the first studied antigen for nuclear medicine purpose is the carcinoembryonic antigen (CEA). Different anti-CEA mAbs have been radiolabeled for therapeutic applications with  and CD3 . AMG211 g method , 64 withg method  or breasg method  with thi64Cu-anti-CA6-Fab was clinically used in ovarian and breast cancer .Finally, as another example to illustrate the large and recent evolution of immuno-PET capacities, cancer antigen 6 (CA6) can be targeted with a radiolabeled Fab . CA6 is 89Zr-trastuzumab in HER2-positive metastatic breast cancer and has shown the immuno-PET capacity to detect most of the known lesions and some that had remained unnoticed with other diagnostic modalities . Based on this first encouraging results, many clinical trials (89Zr-trastuzumab in breast tumor and in their metastatic lesions. The results have shown medium sensitivity of 75.8% (57.7–88.9%) and specificity of 61.5% (31.6–86.1%). These scattering of preliminary results seems to be explained by the high liver uptake which is strongly dependent of the non-radiaocative mAb injected. Indeed, when the authors remove the liver metastases from their interpretation, the SUVmax appears to be significantly higher in HER2 positive compared to HER2 negative patients. In this study, immuno-PET approach demonstrated its ability to identify the intrapatient heterogeneity of 89Zr-trastuzumab uptake in 20% of patient with multiple lesions. This intrapatient heterogeneity could be explained by sampling error during biopsy, heterogeneous intratumoral distribution of HER2 antigen or expression change of HER2 status since the last biopsy  of mAbs in the tumor mass comparatively to the ex-vivo glass-slide immunohistochemistry (IHC) provided by cytology  which receiving antibody drug conjugate such trastuzumab emtansine (T-DM1) as second line treatment of HER2+ metastatic breast cancer (18F-FDG and 89Zr-trastuzumab) patterns and allows a very good prognostic in response evaluation. To optimize the radiation safety and patient radiation dose, copper-64 was used by Mortimer et al.  is currently in progress to determine the ability of 64Cu-trastuzumab immuno-PET to detect positive brain metastases of breast cancer. HER2 antigen is also overexpressed in ~20% of esophagogastric adenocarcinoma and 89Zr-trastuzumab showed promising results  in patients with HER2 positive tumors . In regards of the nanobodies applications, a phase I study confirmed the capacity of 68Ga-HER2-nanobody to provide safe and informative uptake in breast carcinoma  which is particularly overexpressed in breast cancer. In 2010, Dijkers et al.  reportedl trials , 71 havet biopsy . Neverthcytology . A possicytology . The tum lesions , 73. Nevt cancer . The ZEPr et al. –79. 64Cuhan 89Zr . A promie tumors . Same prarcinoma .124I then by 89Zr  is currently under clinical trial  to determine the safety, pharmacokinetic, whole body distribution and radiation dosimetry of this possible new immuno-PET modality.Despite the very large number of clinical trials using small molecules, the Prostate-Specific Membrane Antigen (PSMA) can also be targeted by mAbs. PSMA is particularly overexpressed in prostate adenocarcinoma and J591 mAb was firstly radiolabeled by  by 89Zr . The fir9Zr-J591  showed adalities . In pros89Zr-cetuximab  for an enlightened choice of the most effective treatment between cisplatin or cetuximab  where etuximab  has provetuximab , 88.− radioimmunotherapy (RIT) applications with 90Y or 131I radiolabeled mAbs. At the same period, 86Y has gained interest as an interest surrogate for immuno-PET complement of 90Y-ibritumomab-tiuxetan RIT  was scheduled but withdrawn without explications in non-Hodgkin lymphoma and could, in a near future, provide new information for immuno-PET development. Daratumumab is a mAb that targets CD38, an antigen overexpressed in nearly all myeloma cells. 89Zr-daratumumab was synthesized and showed in a first-in-human study  a highly sensitive detection of multiple myeloma. These preliminary results allowed a good bone localization before therapy, the quantification of the disease burden before therapy, the best responders for “cold” daratumumab therapy and a detection of minimal residual disease after therapy  showed a better concordance . A future phase II clinical trial is scheduled to determine the sensitivity and the specificity of 64Cu-daratumumab in multiple myeloma.Blood cells and hematopoietic stem cells located in bone marrow are well-known to be radiosensitive. As a consequence, hematological diseases such as B-cell non-Hodgkin lymphoma or multiple myeloma are highly studied malignancies in nuclear medicine. Twenty years ago, overexpressed B-lymphocyte antigen CD20 provided an interesting target for βetan RIT . Due to labeling . 89Zr-ripression  with a p therapy . Daratumcordance  between 89Zr (89Zr-DfIABM2C). Phase I clinical trial showed promising results in 15 patients to predict early response to immunotherapy  were done (or in progress) with 89Zr-penbrolizumab and has shown uptake in tumor lesions correlated with treatment response (89Zr-atezolizumab (directed against PDL1) in lobular breast cancer during the ImaGelato clinical study    or with g cancer .89Zr-labeled bevacizumab was prepared and administered in patients with non-small cell lung cancer and showed a correlation between tumor-uptake and progression-free survival and overall survival after treatment  secretion. VEGF receptors located at the surface of the endothelial cells can be targeted by mAbs such bevacizumab. reatment .Today, the immuno-PET field is rapidly progressing and allows to provide essential information for the care management of each patient. To meet the need of personalized medicine era where each patient is unique, immuno-PET provides repeatable, non-invasive whole-body information of biomarkers mapping. Many preclinical developments and clinical proof-of-concepts have been done or are ongoing. The recent clinical developments of immuno-PET have confirmed the potential of mAbs (and their derivatives) as companion diagnostic to determine, whether or not, a patient will respond to a targeted therapy. Nevertheless, the majority of proof-of-concept clinical studies have been performed on small patient samples and require larger studies to confirm their potential as predictive imaging biomarkers. Currently, the main limitation for these clinical studies with great patient numbers are often limited by the costs and the availability limitation of isotopes.in vivo access of several pieces of information on the tumor aggressivity associated to a patient outcome prognostic. The power of this molecular imaging modality seems to be able to show very informative data on the intra-tumor and intra-patient variability on molecular biomarkers expression and consecutively in phenotypic heterogeneity of the entire disease burden. Moreover, in comparison with “gold-standard” biopsies, immuno-PET allows to acquire in-vivo knowledge of the intra-tumoral penetration/biodistribution of the mAb without inherent-risk of tumor seeding during needle biopsy  radiolabeling the same mAb is very promising because the same distribution/pharmacokinetic is expected. Immuno-PET allows in theranostic the determination of the patient dosimetry to optimize the cumulated activity and to predict the therapy response by a quantitative measurement of the tumor-antibody uptake. Molecular imaging by immuno-PET with mAbs or their derivatives will play a pivotal role in the close oncologic future to tailor a customized therapy for each patient.Beyond the image information, immuno-PET is attractive to study the in-vivo behavior of antibody-based therapies and for understanding their therapeutic efficacities. Within the scope of theranostic approach, the use of βCB, CR, FK-B, and CB-M are nuclear medicine physicians. They have worked for many years on the development of immuno-PET approach in oncology. AL is an endocrinologist with an expertise in immuno-PET approach for neuroendocrine tumors. MC is pharmacist, head of the nuclear oncology research team, with a broad expertise in immunology. MB is radiopharmacist with a long term wide experience of radiopharmaceutical development, mainly for immuno-PET applications. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: This trial was designed to assess the treatment effects of granulocyte colony-stimulating factor (G-CSF) and transcutaneous electrical acupoint stimulation (TEAS) on thin endometrium in frozen-thawed embryo transfer (FET) cycles.Methods: Ninety-nine patients with previous cancellations of embryo transfer were included, 56 of whom were prospectively treated with intrauterine perfusion of G-CSF in subsequent FET cycles. The selected patients were randomized into the G-CSF perfusion only group and the G-CSF perfusion combined with TEAS group. The other 43 patients were retrospectively included as controls.Results: Compared to previous cycles, endometrial thickness was statistically significantly increased in the two treatment groups . The increases in endometrial thickness suggested that no statistically significant difference was found between the two treatment groups. The G-CSF with TEAS group suggested a higher embryo implantation rate than the G-CSF perfusion only and control groups . The G-CSF combined with TEAS group demonstrated nominally higher clinical and ongoing pregnancy rates than the G-CSF perfusion-only group and controls, though, the difference was not statistically significant.Conclusion: G-CSF has a potential role in improving endometrium thickness in patients with thin unresponsive endometrium in FET treatment cycles. In addition, when combined with TEAS, G-CSF perfusion treatment also improves the embryo implantation rate; however, randomized controlled trials are highly demanded to provide high-grade evidence regarding clinical pregnancy rate after G-CSF perfusion treatment. Endometrial thickness plays a major part in embryo implantation. Some studies have shown that adequate endometrium (more than 7 mm and preferably 9 mm) is a key precondition for successful implantation. Endometrium thickness below 7 mm is widely considered not preferable for embryo transfer and is associated with decreased pregnancy rates . Variousin vitro fertilization (IVF) population with cycle cancellations due to thin endometrium that is unresponsive to regular therapies or whether there are safer and more effective therapies to improve IVF outcomes in these patients.Granulocyte colony-stimulating factor (G-CSF) is one of the cytokine family members including colony-stimulating factors. It has been reported to have effects on embryo implantation and development and contribute to stromal cells decidualization and trophoblast cells invasion into the maternal tissue , 4. StudAs a non-drug and non-invasive therapy, transcutaneous electrical acupoint stimulation (TEAS) has been widely accepted by many infertile women as a complementary treatment in IVF centers in China . It has Given the endometrial proliferation of C-GSF and endometrial receptivity improvement of TEAS, the question arises whether G-CSF combined with TEAS may improve embryo implantation and ongoing pregnancy rates in women with unresponsive thin endometrium. The current study is designed to answer this question.Ninety-nine patients with previous IVF cycle cancellations due to unresponsive thin endometrium were enrolled in the present study at the reproductive department of the Second Affiliated Hospital of Chengdu University of T.C.M. from May 2017 to October 2019. This trial was performed with the permission of the hospital ethics committee, and a written informed consent was given to each participant.Endometrial thickness was measured with transvaginal ultrasound in the longitudinal plane, at the widest section of the endometrial stripe and the myometrium of the central longitudinal axis of the uterus. Thin unresponsive endometrium was defined as one with a thickness <7 mm on the day of triggering ovulation in fresh cycles or one that is resistant to treatment for more than 10 days with the maximum dose of estradiol administered orally and vaginally  and with vaginal sildenafil citrate in hormone replacement treatment (HRT) cycles. The thin unresponsive endometrium referred to in the present study was defined as the thickness of endometrium that would not increase any more after reaching a certain extent (<7 mm), though, at a high blood level of estrogen.Inclusion criteria were as follows: women aged 20–40 years (a) with a basal FSH concentration □10 IU/L, (b) with at least one cycle cancellation due to thin unresponsive endometrium in IVF treatment, (c) without any other endometrial problems  identified by diagnostic hysteroscopy, and (d) with no contraindications for G-CSF intrauterine perfusion . During the trial period, patients with unresponsive thin endometrium were given options as follows: (a) canceling embryo transfer and receiving endometrium treatment in sub-sequent frozen-thawed embryo transfer (FET) cycle and (b) transferring the embryo into an inadequately thick endometrium. About 56 women who met the inclusion criteria and agreed to accept G-CSF and TEAS treatment in subsequent FET cycles were prospectively enrolled. Patients were randomly assigned to the G-CSF perfusion combined with TEAS group and the G-CSF perfusion only group by a computer-generated randomization table. Forty-three women with thin endometrium who underwent FET with HRT protocols, during January 2016 and May 2017, were retrospectively included as controls according to the inclusion criteria (a), (b), and (c). The controls who received special treatment other than estrogen during the period of endometrium preparation were excluded.The endometrium was prepared with HRT protocol in all FET cycles, in which, estradiol and progesterone were administered sequentially to mimic the natural cycles. Estradiol valerate  was taken orally throughout the cycle. The starting dose was 4 mg/day on Day 3, was gradually increased to 10 mg/day, and was maintainedat that level. Endometrial thickness and pattern were monitored with transvaginal ultrasound before each G-CSF perfusion treatment. Transvaginal progesterone gel  was started on Day 18 of the cycle, at a dose of 90 mg/day, and continued until the pregnancy test 2 weeks after embryo transfer.Granulocyte colony-stimulating factor was perfused into the uterine cavity on Day 8, 11, 14, and 17 of the cycle . The infTranscutaneous electrical acupoint stimulation was performed in the G-CSF combined with TEAS group at acupuncture points SP8 (Diji), PC6 (Neiguan), GV20 (Baihui), ST29 (Guilai), and LR3 (Taichong). The acupoints were determined with reference to the 2nd edition of the Standard Acupuncture Nomenclature (WHO Standard Acupuncture Point Locations in the Western Pacific Region). TEAS was performed by an electro stimulator  through self-adhesive skin electrodes. The disperse-dense wave and 2 Hz in frequency were selected. The intensity range was set at 10–20 mA, depending on the discomfort intolerance. Stimulation reaction  was elicited. Each therapy session lasted for 30 min, during which intensity would be reevaluated every 6 min and reset if necessary. TEAS treatments were administered every other day between Day 3 of the cycle and the day of embryo transfer, equaling a total of six times. The TEAS treatment was operated by two experienced Chinese medicine practitioners in this hospital.Embryo quality was assessed morphologically by the percentage of cytoplasmic fragmentation, number of blastomeres, and symmetry. Day 3 good embryos were defined as the eight-cell stage with <15% fragmentation. Day 5 good embryos were defined as expanded blastocysts with at least grade B trophectoderm and inner cellmass.The clinical pregnancy rate was the primary outcome. Clinical pregnancy was defined by the detection of a gestational sac and fetal heart on ultrasound examination at 6–8 weeks of gestation. Ectopic pregnancies were not included as clinical pregnancies. The secondary outcome is endometrium thickness and embryo implantation rate. Embryo implantation rates were evaluated by the number of gestational sacs seen on ultrasound at 7–8 weeks per the number of embryos transferred. Ongoing pregnancy was defined as a pregnancy proceeding beyond 20 weeks gestational stage.t-test, an ANOVA, and the Kruskal-Wallis test. The categorical data were compared by using Fisher's exact test and the chi-square test. A p-value smaller than 0.05 was considered statistically significant.All analyses are conducted using SPSS 18.0. Continuous data were presented as mean ± SD and compared by using a P = 0.044).Baseline characteristics of the patients included are displayed in P = 0.126). In the two treatment groups, the endometrium thickness was statistically significantly increased after treatment . However, in the patients treated with G-CSF perfusion, adjuvant TEAS did not contribute to an increase of the endometrial thickness .A comparison of endometrial thickness in patients before and after treatment of TEAS and (or) G-CSF perfusion in FET cycles is documented in p = 0.811, 0.910, and 0.523). The G-CSF combined with the TEAS group had a significantly higher embryo implantation rate than the control group ; however, in patients treated with G-CSF perfusion, TEAS did not achieve a higher implantation rate . In addition, the increase in implantation rate in the G-CSF perfusion only group, while nominally greater than the controls, was not significantly different . Comparative analysis of the three groups did not suggest any significant difference in rates of clinical pregnancy, of spontaneous abortion, and of ongoing pregnancy, though, there were nominally higher rates in the G-CSF perfusion combined with TEAS group than the other two groups  in previous IVF cycles, while some had suffered from several canceled cycles due to thin unresponsive endometrium (?7 mm). Therefore, we cannot conclusively rule out the possibility that the effects of G-CSF perfusion combined with TEAS in a large sample size study may be more noticeable. The noteworthy nominal advantages of TEAS treatment in favor of patients with G-CSF intrauterine perfusion may point toward that possibility. As noted above, whether G-CSF combined with TEAS, indeed, improves endometrium proliferation and pregnancy outcomes compared with G-CSF treatment only remains, however, to be determined and is subject to further studies.Reproductive outcomes are the main indicators for clinicians to assess the therapeutic effects of G-CSF perfusion; however, we failed to obtain a higher implantation rate in the G-CSF perfusion-only group compared with controls. Therefore, we could speculate that an increase in endometrial thickness may not be the only factor contributing to a higher embryo implantation rate. The previous study has confirmed that probably 60% of implantation failures in IVF cycles are attributed to poor endometrial receptivity . TherefoThere are also some limitations in the current study. First, the sample size (but a highly selected patient population) is not large enough and the control is retrospective, which is primarily due to the low morbidity rate of thin resistant endometrium and strict inclusion criteria. It is suggested that it is not practical to recruit a large patient population from one center in about 2 years. Due to the selection bias based on the inclusion method of the patient, the results of the study should be interpreted cautiously. Second, most of the included patients were at a young age with normal ovarian function. Therefore, the conclusions may not apply to all women with thin endometrium, especially to older women than those investigated in this study, and cautions should be taken in over-interpreting these results.Granulocyte colony-stimulating factor intrauterine perfusion can significantly improve endometrium thickness in women with thin unresponsive endometrium in FET cycles. The present study does not suggest a beneficial influence from G-CSF perfusion on pregnancy outcomes; however, when combined with TEAS, G-CSF perfusion has a positive effect on embryo implantation. In addition, randomized controlled trials are highly demanded to provide high-grade evidence regarding the clinical pregnancy rate after G-CSF perfusion treatment.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the hospital ethics of Reproductive & Women-Children Hospital, Chengdu University of Traditional Chinese Medicine. The patients/participants provided their written informed consent to participate in this study.LS designed the research and wrote the manuscript. XS and QZ conducted the fieldwork and analyzed data. SZ revised the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


MYRF gene, who had five episodes of encephalopathy. She experienced reduced consciousness, numbness in the arm, and impaired verbal communication from day 4 of SARS-CoV-2 infection. Magnetic resonance imaging of her head showed reduced water diffusion in the corpus callosum and deep white matter. These features were similar to those seen in her previous episodes of encephalopathy. She was treated with methylprednisolone pulse therapy and recovered completely within a week.We report a 14-year-old girl with a heterozygous p. Gln403Arg variant in the  Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily causes respiratory symptoms, but various other organs are also involved. Increasing numbers of neurological complications have been reported in COVID-19  is an infection-associated encephalitis/encephalopathy syndrome  that is patients . MYRF enWritten informed consent for this publication was obtained from the patient and her parent.MYRF had been identified . SARS-CoV-2 infection was diagnosed by polymerase chain reaction (PCR) test of a nasal swab. PCR of cerebrospinal fluid was not performed. Her headache gradually improved with supportive treatment; however she complained of numbness in her arms. On the fourth day after the onset, she developed generalized spasticity, speech disturbance, and had a fixed gaze eyes wide open. Smooth pursuit was preserved. She appeared to understood the spoken word, but was unable to speak herself. These manifestations were similar to those of her previous episodes of MERS . Brain mThere have been a few reports of MERS associated with SARS-CoV-2 infection in children , 9, 10. MYRF variant. A luciferase assay revealed diminished transcriptional activity of the N-terminal region of MYRF by introducing the p.Gln403Arg variant, found in this patient  and the JSPS KAKENHI (18K07890 and 21K07810).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The emergence of COVID-19 triggered the massive implementation of non-pharmaceutical interventions (NPI) which impacted the circulation of respiratory syncytial virus (RSV) during the 2020/2021 season.A time-series susceptible-infected-recovered (TSIR) model was used early September 2021 to forecast the implications of this disruption on the future 2021/2022 RSV epidemic in Lyon urban population.When compared to observed hospital-confirmed cases, the model successfully captured the early start, peak timing, and end of the 2021/2022 RSV epidemic. These simulations, added to other streams of surveillance data, shared and discussed among the local field experts were of great value to mitigate the consequences of this atypical RSV outbreak on our hospital paediatric department.TSIR model, fitted to local hospital data covering large urban areas, can produce plausible post-COVID-19 RSV simulations. Collaborations between modellers and hospital management (who are both model users and data providers) should be encouraged in order to validate the use of dynamical models to timely allocate hospital resources to the future RSV epidemics. The emergence of COVID-19 triggered the massive implementation of non-pharmaceutical interventions (NPI) which impacted the circulation of respiratory syncytial virus (RSV) ,3. TheseSimple mathematical models have been used to predict pre-COVID-19 incidence patterns of childhood infections in large metropolitan centres . The timIn the Lyon metropolitan centre (1.5 million inhabitants), the 2020/2021 RSV epidemic started with a four-month delay, was smaller than previous winters, and was followed by an unusual RSV circulation until early September 2021 ,8.The TSIR model  was usedThe TSIR model was fitted to the demographic data of Lyon and the number of RSV positive tests from week 1/2010 to week 36/2021 to estimate the weekly seasonal transmission rates. Forward simulations were then generated, using the previous estimate parameters fitted to the 2021 demographic data of Lyon and including the different NPI control periods as previously described ,6. The mStatistical analyses were performed using R software version 4.1.0 with the following packages .Compared to the pre-COVID-19 outbreaks, the simulation was characterized by an increase in the peak incidence and an earlier timing of this peak at week 48/2021 . The simulation in week 36/2021 was used to inform the paediatric department and a close monitoring of the RSV situation was initiated. The RSV epidemic was soon declared on week 41/2021, closely matching the simulation  (When compared to hospital-confirmed cases, the model successfully captured the early start, peak timing, and end of the 2021/2022 RSV epidemic. This information was critical to increase readiness regarding the weekly RSV surveillance data.In the study context, although there are clear advantages of this simple TSIR model such as the existing literature on its use ,6, the aThe increase in the peak incidence was caused, in the simulation, by an increase in the proportion susceptible children in the population, due to a softened 2020/2021 RSV epidemic (The current global RSV situation emphasizes the need for plausible simulations that can be combined with the different streams of surveillance data and field expertise to timely allocate adequate local hospital resources to RSV epidemics. Further research is needed to define good modelling practices for the hospital setting. This represents an opportunity to strengthen the collaboration between modellers and hospital clinical management, who are both data providers and model users. Healthcare professionals could benefit from open access, easy-to-use, forecasting models that produce plausible RSV simulations with limited data set requirements, while modellers could benefit from direct access to comprehensive databases and the expertise of health care workers.


BackgroundThe ability to provide performance insights of various United States Medical Licensing Examination (USMLE) Step 1 assessments is of great importance to medical educators. Two custom pre-clerkship assessments used at the Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas (KSOM) are National Board of Medical Examiners (NBME)-derived end-of-semester final examinations and subject examinations. The authors sought to determine if performance on these custom assessments can provide feedback on a medical student’s readiness to undertake the USMLE Step 1 examination.MethodologyDeidentified student performance data were provided by institutional databases for the KSOM graduating class of 2023 (N = 60). Pearson correlation analyses were utilized to evaluate the strength of the correlation between USMLE Step 1 performance and NBME subject examinations versus NBME end-of-semester final examinations.ResultsThe results indicated that the NBME end-of-semester final examinations have a statistically higher correlation to the USMLE Step 1 score than the majority of the individual NBME subject examinations. However, the mean NBME subject examination score  demonstrated significantly higher correlation to the USMLE Step 1 performance than the NBME end-of-semester final examination score for both Semesters 1 and 2 .ConclusionsThese results showed that the mean of the NBME subject examination score was a better metric to assess readiness for the USMLE Step 1 than the NBME end-of-semester final examinations. However, each NBME end-of-semester final examination score showed a better correlation than the majority of the NBME subject examinations. Medical schools prioritize methods in which they can guide and assess their students for success . ObjectiWhile successful completion of USMLE Step 1 is multifactorial, the aim of this study is focused on pre-clerkship examination metrics and their value in providing feedback to students as they navigate their pre-clerkship medical school years. Determining indicators of success on the USMLE Step 1 is of great importance because this information would allow interventions to be provided to address identified deficiencies ,8. AddreThe Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas (KSOM), which has an 18-month pre-clerkship curriculum that spans three semesters, uses various performance assessments. At the KSOM, the following three pre-clerkship performance assessments are used: (a) National Board of Medical Examiners (NBME) subject examinations, (b) NBME end-of-semester final examinations, and (c) Comprehensive Basic Sciences Examination (CBSE). The NBME subject examinations and end-of-semester final examinations are assessments that the KSOM faculties derive from the NBME item bank. In contrast, the CBSE is a standardized practice examination developed by the NBME for the USMLE Step 1 that many schools administer .While the NBME-customized subject examinations and CBSE are relatively common in medical education, the end-of-semester final examinations are not widely used . SeveralBetween the NBME subject examinations and NBME end-of-semester final examinations, we seek to identify which of these custom assessments provides better feedback in assessing content mastery and overall preparedness of the students for the USMLE Step 1. We hypothesize that NBME end-of-semester final examinations would provide better insight regarding USMLE Step 1 performance than the NBME subject examinations.Deidentified student performance data and demographic information were provided by institutional databases with an approved Institutional Review Board (IRB) protocol. The first two years of the pre-clerkship curriculum were the focus of this study Figure . The datAt the end of the first two pre-clerkship semesters, a 60-item NBME end-of-semester final examination was administered that comprehensively covered the content of all organ systems covered within a semester. The customized examination was built with an evenly distributed number of faculty-selected NBME questions for each system to allow for individual evaluation. An overall passing threshold of 70% was required for every student, as well as a passing threshold of 70% for individual systems covered on the final examination for students who needed to remediate the section. To successfully progress through the curriculum, students were required to meet the 70% passing thresholds for all NBME subject examinations as well. The CBSE is administered to conclude the end of the third semester.A Pearson correlation analysis was performed to investigate the relationship between NBME end-of-semester final examination scores and USMLE Step 1 performance, as well as the NBME subject examination scores and USMLE Step 1 performance. Statistical significance was set at p-value ≤0.05. All calculations were done using SPSS version 26.0 . This study was approved by the KSOM Biomedical Institutional Review Board .Data from 60 students in the class of 2023 were collected. Presented in Table A Pearson correlation analysis was performed to examine the relationship between the examinations taken by the class of 2023 during the pre-clerkship phase at the KSOM , Gastroenterology, Endocrine, and Reproductive - Exam 4 (r = 0.261), Cardiovascular, Pulmonary, and Renal - Exam 2 (r = 0.176), Mind, Brain, and Behavior - Exam 1 (r = 0.174) and Mind, Brain, and Behaviour - Exam 3 (r = 0.157).The mean NBME subject examination scores for each semester showed significant correlation ranging from 0.316 to 0.582 to the USMLE Step 1 examination was observed for Semester 1 (p < 0.000), Semester 2 (p < 0.001), and Semester 3 (p < 0.017). The mean of all the NBME subject examinations taken was calculated, and a correlation of 0.662 to the USMLE Step 1 performance was identified (p < 0.001).Semester 1 NBME end-of-semester final examination showed a correlation of 0.504 (p < 0.001), while Semester 2 revealed a correlation of 0.475 (p < 0.001). Both NBME end-of-semester final examinations demonstrated a lower correlation than the mean of the NBME subject examinations at the end of each semester.At the end of Semester 3, a CBSE assessment that addressed all the objectives throughout the pre-clerkship curriculum was administered to the class of 2023 medical students. A correlation (r) of 0.824 (p < 0.001) was found between the CBSE and USMLE Step 1. The mean of all the examinations including the CBSE has a correlation (r) of 0.718 (p < 0.001). This is higher than what was observed for the mean NBME subject examinations.Results obtained from the analyses indicate that the NBME subject examinations administered during the pre-clerkship phase of the medical education curriculum at the KSOM demonstrated a varying but mostly significant correlation to the scores on the USMLE Step 1 examination. The correlation between the NBME system examinations and the USMLE Step 1 examination provides some degree of validation of the NBME subject examinations as an assessment tool for a student’s medical knowledge. Additionally, the overall performance on these subject examinations across all systems during the pre-clerkship curriculum provided a better insight into a student’s overall content mastery and preparedness to take USMLE Step 1.On the other hand, the NBME end-of-semester final examinations administered at the end of each semester are another method used by KSOM to assess the academic aptitude of their medical students. Due to the similarities in item format and content scope, the CBSE has been established as a standard method of assessing a medical student’s success in the USMLE Step 1 examination . Our datBoth NBME end-of-semester final examinations administered at the end of the first and second semesters also demonstrated a significant correlation to USMLE Step 1 scores. However, these correlations are lower for the corresponding mean NBME subject examinations for the same semester. These findings are not in congruence with our hypothesis that the NBME end-of-semester final examinations will provide better feedback regarding USMLE Step 1 performance than the NBME subject examinations.One potential explanation for this outcome is that the mean NBME system examinations have a better potential in capturing competency about a system than the end-of-semester final examination. This result may be due to the higher aggregate number of questions taken on all the NBME system examinations throughout the semester. Additionally, the NBME end-of-semester final examinations are secondarily used as a remediation tool for students who failed one or more of the NBME system examinations. Students who have successfully passed all the NBME subject examinations within the semester might be inclined to prepare only to obtain a passing score. Lastly, the preparation time for the NBME end-of-semester final examinations is significantly less in comparison to each NBME system examination.We initially inferred that the NBME end-of-semester examinations would show a more meaningful relationship with USMLE Step 1 performance. With the expectation of being tested regarding the same concept at different levels during the pre-clerkship curriculum, with the USMLE Step 1 as the ultimate step, we also expected that this outcome would result in improved retention and recall of the learned information. This idea is further supported in that initial tests enhance long-term retention and final test performance . HoweverIn a survey of medical schools, the end-of-semester final examination is an assessment method not widely utilized by medical schools within the United States . The resWe recognize several limitations within our study. First, the interpreted data was derived from a small sample size and the scope of the study covered a single cohort at a single medical school. Furthermore, the student demographics for the study sample included over 50% of students who identify as non-white, 17% ethnically underrepresented in medicine, 30% first generation, and 37% economically disadvantaged. This range shows the large diverse population at KSOM, which could impact the generalizability as it relates to the demographics at other medical schools. Second, the curriculum structure is not consistent across all medical schools. KSOM endorses an accelerated program that prepares students to enter dedicated USMLE Step 1 preparation after 18 months and requires them to take the USMLE Step 1 by the end of Year 2, which is earlier than most schools.Further validation of the data we provided could be granted through multi-cohort and multi-institutional analyses to compare results. It will also be important to analyze future metrics to determine how effective these correlations are across time and for clinical performance. Meaningful information could be gathered by following cohorts through the completion of the medical school curriculum and obtaining information on shelf examination scores, USMLE Step 2 performance, and residency program matching. This information could be compared across institutions to examine how pass/fail curriculums compare to graded curriculums. Other future studies should look to identify other variables that could give further insight regarding USMLE Step 1 performance, such as subgroup analyses on different student backgrounds.This study aimed to identify the most appropriate examination metric to utilize when assessing a medical student’s preparedness for the USMLE Step 1 during the pre-clinical curriculum. Although significant correlations were observed between the different forms of assessments and USMLE Step 1, performance on the NBME subject examinations provided the most insight regarding a student’s readiness to undertake USMLE Step 1. Identifying substandard performance in any of these subject examinations necessitates early interventions to maximize the student’s likelihood of obtaining a passing USMLE Step 1 outcome.


Hematopoietic stem cells (HSCs) provide a life-long supply of haemopoietic cells and are indispensable for clinical transplantation in the treatment of malignant hematological diseases. Clinical applications require vast quantities of HSCs with maintained stemness characteristics. Meeting this demand poses often insurmountable challenges for traditional culture methods. Creating a supportive artificial microenvironment for the culture of HSCs, which allows the expansion of the cells while maintaining their stemness, is becoming a new solution for the provision of these rare multipotent HSCs. Hydrogels with good biocompatibility, excellent hydrophilicity, tunable biochemical and biophysical properties have been applied in mimicking the hematopoietic niche for the efficient expansion of HSCs. This review focuses on recent progress in the use of hydrogels in this specialized application. Advanced biomimetic strategies use for the creation of an artificial haemopoietic niche are discussed, advances in combined use of hydrogel matrices and microfluidics, including the emerging organ-on-a-chip technology, are summarized. We also provide a brief description of novel stimulus-responsive hydrogels that are used to establish an intelligent dynamic cell microenvironment. Finally, current challenges and future perspectives of engineering hydrogels for HSC biomedicine are explored. HSCs can differentiate into all types of blood cell in the body . In the shortage .HSCs used in transplantation are mainly derived from umbilical cord blood. These cells can be used with a relatively low risk of immune rejection, while the number of cells that can be recovered is limited .ex vivo, for example, supplementing hematopoietic stimulating factors, the addition of small molecule compounds into the suspension culture medium, and co-culture of HSCs and their supporting cells to maintain cell growth enhance the cellular connections  culture conditions in vitro  MSCs and endothelial cells , C-X-C motif chemokine 12 (CXCL-12), and pleiotrophin, synthesized by leptin Receptoral cells . Few HSCal cells . These sal cells . In addial cells . TherefoOsteoblasts are particularly common in the trabecular bone of the endosteum and are important in regulating HSC maintenance . Primiti+ cells (Osteoblasts were one of the first non-hematopoietic BM cells reported to participate in HSPC regulation . Early s+ cells .+ arterioles and capillaries. These vessels anastomose with Sca1- venous sinuses (approximately 50–100 µm in diameter). These venous sinuses drain into the central longitudinal vein running in the BM , arterioles and arteries  increases with age and eventually occupies up to 50% of the BM cavity . Traditi+ regulatory T cells in the endothelial area after transplantation and can survive for 1 month without immunosuppressive drugs  are essential growth factors for HSCs . SCF, al+ HSPCs . CXCL12 + HSPCs . The CXC+ HSPCs .There is evidence to show that the autonomic nervous system (ANS) and SNS can regulate the fate of HSCs . ANS sig6 receptor for homing -HSCs, which are deeply quiescent in niches to maintain self-renewal and multilineage differentiation potential throughout their lives, and short-term (ST)-HSCs, which are maintained in more active niches with limited self-renewal potential . The maiin vitro. Ex vivo expansion methods of HSCs reported in the literatures are often quite different. Even under the same conditions of cytokine combination, the expansion ability and transplantation ability of cells are still significantly differ. The heterogeneity of HSCs also makes it challenging to understand the comprehensive signaling mechanism that defines the balance between homeostasis and self-renewal of among cells. Recent evidence has added new insights into the plasticity of BM niche and mitochondrial network, which synergistically determine the fate of HSCs. However, these new discoveries also increase the complexity and introduce a highly dynamic interrelationship in studies of HSC fate. Therefore, research on the complex mechanisms controlling the fate of HSCs remains limited.Heterogeneity of HSCs is another important reason for the difficulty in their expansion in vivo. However, insufficient amounts limit the clinical application. Ex vivo expansion of HSCs is the basis both for the clinical promotion of UCBT and gene therapy. Therefore, many efforts have been focused on improving HSCs expansion methods.Compared with haplotype hematopoietic stem cell transplantation (haplo HSCT), umbilical cord blood stem cell transplantation (UCBT) can be easily obtained from CB resources. UCBT has high tolerance to human leukocyte antigen HLA mismatch, a high colony forming potential of HSCs and HSPCs, and a low incidence and recurrence rate of graft versus host disease (GVHD) following transplantation. Furthermore, HSCs are ideal vector cells for gene therapy. The long-term self-renewal and self-maintenance abilities of HSCs are conducive to the long-term expression of the target therapeutic genes ex vivo. After 5–8 days of culturing of human CB CD34+CD38− cells in serum free medium containing Fms Related Tyrosine Kinase 3 (Flt-3), SCF, Interleukin (IL)-3, IL-6 and G-CSF, the number of colony forming units (CFU) increased 100 -fold, and the number of long-term culture-initiating cells (LTC-IC) increased 4-fold (in vitro (Ext−IgG (DXI) was used to activate the Notch signal pathway in human CB CD34+ cells to achieve clinically significant in vitro expansion of ST-HSPCs with and shorten the implantation time of neutrophils following transplantation , nicotinamide, stem regin-1 and valproic acid, which simultaneously expand ST- and LT-HSCs, provide effective schemes for HSC amplification in vitro . U1M171,in vitro . In 2014in vitro  were thein vitro . The minIn vitro experiments have shown that MSCs plays an important role in the maintenance and expansion of CD34+ BM cells, but do not affect the erythroid differentiation ability . Sustained activation of CXCR4 receptor in the 32D cells shows the effect of biomolecules on 32D cell migration in the modified PEG-DA hydrogel. A concept of biological cues introduced into the hydrogel well for HSC culture was revealed, while experiment on the measurement of more HSC biomarkers has been limited.via a microfabrication patterning technology assisted by a photomask and photoresist. Proteins and peptides including the key cytokines, SCF, interferon-g (IFNg) and RGDS connecting segment 1, were chemically modified onto PEG with certain ratios to form the PEG-protein and PEG-RGDS composite. The composite was immobilized on the well surface via a photo-induced linking reaction. C-kit+ cells collected from mouse BM cells were cultured in the PEG-DA hydrogel wells. After 2-week culture, the cell number increased by 11.6–19.0% for cells 3D encapsulated in hydrogel, which is higher than that in 2D culture, and 53.8% cells remined c-kit+ without an observed loss. Encapsulated c-kit+ cells could form all colonies which had similar results to that of 2D culture. However, 3D culture exhibited a larger number of multilineage HSPC-derived colonies than that of 2D culture. These experiments demonstrated that cytokines encapsulated in a 3D scaffold better replicated the cell–matrix interactions and showed advantages in controlling diffusion in cultures designed for LT-HSC expansion compared with the 2D hydrogel  from mature BM (Lin+) cells. The covalent incorporation ensured that the GelMA hydrogel retained its SCF content for longer than 7 days. The stable provision of this critical growth factor was sufficient to support the proliferation and lineage differentiation of HSCs.This research group also fabricated a HSPC culture substrate with the derivatives of PEG-DA hydrogels. PEG-DA hydrogel wells were fabricated hydrogel   to detect the amplification frequency of medium and LT-HSCs; after 24–30 weeks of transplantation, the amplification frequency of LT-HSCs cultured in ZTOpt mode was much higher than that of other culture methods. Both LDA and secondary transplantation experiments showed that LT-HSC cells with long-term hematopoietic function could be cultured and expanded by ZTG. The LT-HSCs expanded in ZTG hydrogel were injected into immune-deficient NSG mice for primary and secondary BM transplantation. The experimental results showed that in HSPCs derived from CB, CD34+ was effectively amplified in ZTG hydrogel; the expanded HSPCs were used for BM transplantation, which also showed good amplification performance in vivo.Zwitterionic materials have attracted attention recently due to their structural similarity to naturally occurring cell membrane lipids. in vitro expansion of HSCs mostly focused on the role of the ECM, while the effects of the metabolism of the HSCs themselves has received very little attention -MSC niche II, indicating that UC-MSC stimulated HPC differentiation. In niche II, expression of the pan-leukocyte marker CD45, and CD13 were observed, whilst CD56 was poorly expressed in niche II and myeloid differentiation was increased. The researchers established a collagen hydrogel-based artificial HSC niche with two statuses: HPCs in niche I are a proliferative and contained cell population of CD34+/CD38- maturing myeloid cells , while HPCs in niche II contained high numbers of primitive CD34+/CD38- phenotype cells beginning myeloid  differentiation, resembling the endosteal part of the BM niche. These authors also reported that UC-MSCs were not appropriate feeder cells as they caused extensive differentiation and a complete loss of primitive HSC phenotype  were loaded into the HAMA hydrogel by mixing the CNTs suspension with HAMA and LAP in pre-gel solution and followed by a photo-cross-linking. CNT hybrid hydrogels showed better hydrophilicity because of the abundant carboxyl groups from the CNTs. CNTs also improved the modulus of the hydrogels from 5.0 to 7.5 kPa. Isolated CD34+ cells were cultured on the hydrogels supplied with the cytokine cocktail. HSC release of ROS decreases the survival of HSCs and causes the activation of HSCs. In the CNT-loaded HAMA hydrogel, ROS triggers the biodegradation of polysaccharides in the hydrogel, releasing the CNTs to scavenge ROS. The percentage of CD34+CD38− and CD34+ cells increased in the CNT hybrid hydrogel after 10 days of culture. CNT hybrid hydrogels also significantly promoted the total CFU, CFU-GM, and CFU-GEMM compared with non-CNT loaded hydrogels, indicating that integrating nanomaterials with antioxidant properties is beneficial for the hematopoietic function of HSCs. Another study combined methacrylated graphene oxide (MeGO) with HA hydrogels, which significantly increased the water absorption and elastic modulus of the hybrid material. The composite MeGO-HA matrix supported the proliferation of CD34+ cells, whilst maintaining their primitive CD34+CD38− phenotype, especially in a version containing 0.05% w/v MeGO . They presented a 3D niche biomimetic model by fabricating an engineered double-layered bead with an alginate-based inner layer and a Puramatrix-based out layer. Numbers of CD34+ cells significantly increased at weeks 6–7, reaching to a maximum level at week 7 of approximately 4-fold that of week 1–2; it then gradually declining at week 8. At week 4, most cells were functional and remained in an undifferentiated status; however, there was a slight CD20 and CD38 signal for lymphoid differentiation, and CD33 signal for myeloid differentiation, as well as CD34+/HLA−DR+ for an intermediate stem cell population. The results indicated this biomimetic niche model had good potential for the long-term culture of HSCs and maintenance on functional cell numbers.Traditional bulk hydrogels are usually relatively large and lack micropores, resulting in slow degradation and limited substance diffusion . Micron-The above methods enabled the microencapsulation of co-cultured HSCs and MSCs with a population distribution approximating that of the natural niche. Encapsulating cells in 3D hydrogels has been demonstrated to regulate stem cell fate decisions by supporting tunable ligand incorporation, the delivery of soluble factors, and mechano-sensing .Microfluidic technology has emerged as a powerful tool in the reconstruction of the cellular microenvironment. This approach enables the creation of micro-sized droplets matching the diameter of the cells and permits the precise microscale manipulation of fluid flow and the modulation of the concentration of various factors . Howevervia both flow and diffusion  through a microfluidic device using a computer-controlled syringe pump to form a GelMA hydrogel containing a covalently fixed SCF gradient, and observed that HSCs expanded with the SCF content gradient. SCF embedded in this 3D environment promoted the proliferation and the maintenance of primitive HSCs in a dose-dependent manner.The use of microfluidic systems can rapidly establish a concentration gradient of various chemical compounds, facilitating the precise control of culture conditions and experimental investigation of the effects of individual factors . Chemicaiffusion . T- or Yiffusion . Mahadik+(GFP+) BM cells mixed in a single hydrogel were imaged using a multiphoton microscope. The spectral deconvolution method could identify LSK cells from mature BM (Lin+) cells. The multiple gradient hydrogel constructs developed here provide the potential for HSC fate manipulation and tracking analysis in 3D microenvironment models, and will become a powerful tool for studying cell–microenvironment interactions (In addition to chemical gradients, microfluidics can also generate cellular gradients to mimic the complex multicellular microenvironment. ractions .The human organ chip is a transformative biomedical technology that was voted as one of the “Top Ten Emerging Technologies” in 2016 . In one in vitro culture, the amount and distribution of HSPCs and HSCs remained similar to those of the fresh BM (+ HSCs and BM-derived MSCs in fibrin gels. The bottom “vascular” chamber was lined by HUVECs and perfused with culture medium containing supportive cytokines (in vitro model preserved stemness and supported myeloerythroid proliferation and differentiation (in vitro are transplanted into mice for evaluation of their safety and their ability to reconstitute BM function (in vitro expanded HSCs without the need to sacrifice live animals.These organ on-a-chip models closely approximate the environment of the natural BM. fresh BM  (Figure fresh BM . Aleman fresh BM . In thisfresh BM . Chou etytokines . Culturintiation . Researcfunction . It is aStimulus-responsive hydrogels are promising tools that can sense signals coming from niche cells and/or cytokines in the matrix and respond to these signals by changes in conductive, chemical, or temperature characteristics. These “intelligent” microenvironments can adapt to the requirements of the cells growing within . For exaStimulus responsive hydrogels can be combined with biosensor technology to directly monitor key markers of living cells cultured in the biomimetic environment. This approach allows for the long-term tracking and monitoring of the encapsulated cells . Lee et While current hydrogel methods enable the massive expansion of encapsulated cells, they are seldom equipped to sense and monitor cell characteristics . Insteadin vitro expansion of primitive HSCs. A combination of various chemical modifications, the addition of biomaterials, and advancements in technologies—such as microfluidics and organ on-a-chip—make it possible to establish hydrogel-based microenvironments with exquisite architecture and adjustable physical features that closely mimic the natural hematopoietic niche. Aside from their clinical relevance, these systems also facilitate studies on the behavior and fate of HSCs. However, due to the extraordinarily complex physiology of the natural hematopoietic niche, replicating it in vitro using engineered hydrogel-based systems still holds many challenges. Various features of the natural hematopoietic environment, such as the presence of other cells, biochemical cues, varying stiffness, and topography, are distributed in a heterogeneous environment and direct the behavior and fate of HSCs though multiple mechanisms. In contrast, most hydrogel-based culture systems exhibit isotropy and lack the anisotropic properties of the tissue microenvironment. Although the integration of hydrogels in microfluidic systems enabled the dynamic co-existence of two distinct cell populations, the gap between these and the natural niche remains wide. BM on-a-chip technology is a promising and powerful tool for ex-vivo HSC culture and the monitoring and scientific exploration of the hematopoietic process. However, in their current iteration, they can only accommodate no more than two distinct cell populations. In addition, their complex manufacturing and high costs currently limit their large-scale production for clinical applications.Hydrogel biomaterials show excellent biosafety, offer flexible possibilities for chemical modifications and biofunctionalization, and have been successfully used for the in vivo niche (In general, hydrogel have uniform internal structures, which differs significantly from the architecture of a natural niche . 3D prinvo niche . A compovo niche . Howeverin vivo, could significantly improve the outcomes of culturing HSCs in vitro.The natural hematopoietic niche contains a viscoelastic matrix, while most hydrogels are primarily elastic materials. These artificial matrices cannot relax under strain forces. In contrast, the natural viscoelastic matrix is mechanically yielding, and the matrix can be dynamically remodeled. The development of better viscoelastic hydrogels, replicating the conditions for cell–ECM interactions in vitro. However, there are very limited to normal HSCs that undergo asymmetric mitosis. HSCs are very sensitive to the environment, which means after leaving the niche, stimulation from the external environment, such as mechanical force or redox reaction, can easily cause their differentiation and loss of the expression of original phenotype markers.HSCs from CB play an important role in clinical transplantation. CB provides an alternative source for allogeneic HSCT patients lacking HLA-matched donors . Comparein vitro. The chemical and engineering strategies and techniques for improving the niche of biomimetic hematopoiesis were summarized. The potential of stimulus-responsive hydrogels in the establishment of an intelligent microenvironment was also described. Finally, the remaining challenges in the use of the hydrogel culture platform and the broad prospects for development were reviewed. The improved artificial microenvironment for HSC amplification in vitro and the bionic BM for testing the safety and effectiveness of HSC treatment are exciting developments, providing new solutions for the increasing use of hydrogel-based HSC culture platforms in clinical applications and scientific research. However, due to the complexity of the niche, in the current technology, it remains difficult to artificially reconstruct all these elements into functional BM. The development of an effective bioengineering strategy requires further research on the molecular mechanism of HSC behavior in the niche and the progression of biomaterial technology.In the previous,


The effects SARS-CoV-2 inflicts on human physiology, especially in patients who developed COVID-19, can range from flu-like symptoms to death, and although many lives have been lost during the pandemic, others have faced the resolution of aggressive neoplasms that once proclaimed a poor prognosis following traditional treatments. The purpose of this review was to analyze several fortunate case reports and their associated biomolecular pathways to further explore new avenues that might provide oncological treatments in the future of medicine. We included papers that discussed cases in which patients affected by COVID-19 suffered beneficial changes in their cancer status. Multiple mechanisms which elicited a reactivation of the host’s immune system included cross-reactivity with viral antigens and downregulation of neoplastic cells. We were able to identify important cases presenting the resolution/remission of different aggressive neoplasms, for which most of the time, standard-of-care treatments offered little to no prospect towards a cure. The intricacy of the defense mechanisms humans have adopted against cancer cells through the millennia are still not well understood, but SARS-CoV-2 has demonstrated that the same ruinous cytokine storm which has taken so many lives can paradoxically be the answer we have been looking for to recalibrate the immunological system to retarget and vanquish malignancies. Since 12 December 2019, when the first symptoms of a new severe upper respiratory disease were reported, later giving rise to the COVID-19 pandemic, the myriad of effects that SARS-CoV-2 can inflict on human physiology have not only been devastating, but also beneficially unforeseen. The vast collection of reported clinical and molecular manifestations have increased due to SARS-CoV-2 exceptional swift capacity to undergo mutations, thus perpetuating the pandemic through the emergence of new variants . The fieThe studies included in this review consisted of three systematic reviews, one meta-analysis, seven case reports, and two case series. A summary of the cases is presented in Although the combined diagnosis of a malignant neoplasm along with COVID-19 might seem like an unfortunate coalescence, our analysis of multiple case reports surfaced a silver lining that could lead to novel treatment options for cancer. In principle, an individual’s immune system should be capable of defeating malignancies through various immune-dependent mechanisms that include both innate and adaptive responses. However, unfortunately, in the presence of certain pathological microenvironments, the host’s defense is unable to optimally perform and, rather, is deviated towards the path for tolerance. Downregulated pathways developed by cancer cells due to the accumulation of driver mutations hinder the cytotoxic effects of immune cells from exerting their effector functions. Some of the tolerance mechanisms interfering with tumor clearing include the downregulation of HLA-I, the promotion of transforming growth factor-B (TGF-B) and vascular endothelial growth factor (VEGF) activity, and the release of IL-10 and IL-6 by cancerous cells, leading to the development and proliferation of malignancies . UnfortuClostridium difficile colitis) prior to COVID-19, leading to a spontaneous regression of a diffuse large B-cell lymphoma of the maxillary sinus [This mechanism was demonstrated in a case report where an extremely rare spontaneous resolution of a pituitary microadenoma occurred secondary to an immune response to COVID-19 . It has ry sinus . Anotherry sinus ; importaAnother possible mechanism explaining the regression of tumors was presented in a review article, stating that molecular mimicry could constitute an important role in tumor reduction and remission. SARS-CoV-2 proteins, including the Spike protein, are mimicked by markers displayed on tumor cells’ surface such as heat shock proteins , therefore eliciting a similar immune response. This mechanism of cross-reactivity could allow cytotoxic T cells and antibodies specifically produced against the virus to also target the cancer cells, leading to the regression of the tumor . HoweverA different mechanism was described in a case series, which presented three patients affected by metastatic colorectal cancer showing evidence of tumor reduction amidst COVID-19 . It is wThe interaction between SARS-CoV-2 and colon cancer cells was hypothesized to happen trough a previously described mechanism that, most likely, guides SARS-CoV-2 infectivity pleiotropism, consisting of an interaction between the S1 protein with the transmembrane receptor neuropilin-1 (NRP-1). Interestingly, co-expression of ACE2 and NRP1 on a human colon adenocarcinoma cell line (Caco-2) led to an increase in infectivity when compared to that observed with cells that only expressed the ACE2 receptor . Tumor rAnother mechanism in which a deep exploration should be conducted to induce the reduction/remission of certain neoplasms is downregulation. In deranged hematological malignancies, such as NK lymphomas, the neoplastic cells develop evasion mechanisms that will inhibit the host’s immune response from direct targeting by CD8+ T cells. However, neoplastic NK cells display an array of inhibitory molecules that can be targeted for downregulation. In the NK lymphoma remission case report , SARS-CoAnother case report of a complete remission of a follicular cell lymphoma amidst COVID-19, illustrated the shrinkage of a para-aortic lymph node . This evAs the field of biotechnology grows, genetically engineered viruses have taken important roles in novel treatment therapies. We propose that a genetically modified version of SARS-CoV-2, in which virulence is significantly diminished, could be used to infect a cancer patient as a form of treatment. This therapeutic mechanism could follow both pathways of upregulation as well as downregulation, depending on the imminent malignancy. In addition, infecting a patient with SARS-CoV-2, which is known to be a lytic virus, will promote the release of its content , thus triggering the immune system via tumor-associated antigens to target the other malignant cells . AlthougTherefore, the addition of IL-6 blockers, as well as of a PD-L1 inhibitor could be useful in cancer treatment whenever previous testing for PD-L1 expression on the resident cells of a tumor has been demonstrated, so that the inhibitor will truly have an effect . This isSeveral mechanisms have been identified in the context of tumor regression amidst COVID-19. At least nine case reports/series were identified in which patients experienced such desirable clinical outcome, which makes the proposal of this article worth considering for the design of future strategies that can successfully treat malignancies which harbor difficulties related to the tumor type or location. Furthermore, a case report with detailed tissue examination confirmed tumor remission after mRNA vaccination for COVID-19. Further characterization of the triggers for a robust immune response is required to design a “perfect fit” for each case. The use of novel biological treatments that can modulate the immune response such as IL-6 inhibitors and immune point blockers could aid in this strategy of a personalized alternative for the treatment of malignancies, with less side effects and higher efficacy.