Exploring the potential of broadband Tamm plasmon resonance for enhanced photodetection.

Tamm plasmon polaritons (TPPs) have emerged as a promising platform for photodetector applications due to their strong light-matter interaction and potential for efficient light absorption. In this work, a design for a broadband photodetector (PD) based on the optical Tamm plasmon (OTS) state generated in a periodic metal-semiconductor-distributed Bragg reflector (DBR) geometry is proposed. The transfer matrix method (TMM) was used to study the propagation of electromagnetic waves through the proposed structure. By exciting the structure with incident light and analyzing the electric field profile within the multilayer structure at the resonant wavelength, we observe a distinctive electric field distribution that indicates the presence of Tamm plasmon modes. A comparative study was conducted to investigate the optical properties of a photodetector in the near-infrared (NIR) range by varying parameters such as thickness. By optimizing the thickness, we successfully achieved a broadband photoresponse in the photodetector, with a maximum responsivity of 21.8 mA/W at a wavelength of 1354 nm, which falls within the photonic bandgap region. FWHM was found to be 590 nm for the responsivity spectrum. The geometry also presents maximum absorption with FWHM calculated to be about 871.5 nm. The proposed geometry offers a broadband photoresponse, which is advantageous for the advancement of Tamm-based detector technologies. The ability to detect light over a wide operation range makes this mechanism highly beneficial for various applications.

N-Heterocyclic imino-catalyzed 1,4-regioselective azide-alkyne cycloaddition (AAC): a metal-free approach.

An unprecedented synthetic approach has been devised to efficiently synthesize regioselective 1,4-disubstituted 1,2,3-triazoles. This technique relies on the use of innovative metal-free highly basic N-heterocyclic imino catalysts. The experimental observations have been supported further by TD-DFT computational studies.

Geo-environmental factors and the effectiveness of mulberry leaf extract in managing malaria.

Malaria prevalence has become medically important and a socioeconomic impediment for the endemic regions, including Purulia, West Bengal. Geo-environmental variables, humidity, altitude, and land use patterns are responsible for malaria. For surveillance of the endemic nature of Purulia's blocks, statistical and spatiotemporal factors analysis have been done here. Also, a novel approach for the Pf malaria treatment using methanolic leaf extract of Morus alba S1 has significantly reduced the parasite load. The EC50 value (1.852) of the methanolic extract of M. alba S1 with P. falciparum 3D7 strain is close to the EC50 value (0.998) of the standard drug chloroquine with the same chloroquine-sensitive strain. Further studies with an in-silico model have shown successful interaction between DHFR and the phytochemicals. Both 1-octadecyne and oxirane interacted favourably, which was depicted through GC-MS analysis. The predicted binary logistic regression model will help the policy makers for epidemiological surveillance in malaria-prone areas worldwide when substantial climate variables create a circumstance favourable for malaria. From the in vitro and in silico studies, it can be concluded that the methanolic extract of M. alba S1 leaves were proven to have promising antiplasmodial activity. Thus, there is a scope for policy-driven approach for discovering and developing these lead compounds and undermining the rising resistance to the frontline anti-malarial drugs in the world.

Parkin Deficiency Suppresses Antigen Presentation to Promote Tumor Immune Evasion and Immunotherapy Resistance.

Parkin is an E3 ubiquitin ligase, which plays a key role in the development of Parkinson disease. Parkin defects also occur in numerous cancers, and a growing body of evidence indicates that Parkin functions as a tumor suppressor that impedes a number of cellular processes involved in tumorigenesis. Here, we generated murine and human models that closely mimic the advanced-stage tumors where Parkin deficiencies are found to provide deeper insights into the tumor suppressive functions of Parkin. Loss of Parkin expression led to aggressive tumor growth, which was associated with poor tumor antigen presentation and limited antitumor CD8+ T-cell infiltration and activation. The effect of Parkin deficiency on tumor growth was lost following depletion of CD8+ T cells. In line with previous findings, Parkin deficiency was linked with mitochondria-associated metabolic stress, PTEN degradation, and enhanced Akt activation. Increased Akt signaling led to dysregulation of antigen presentation, and treatment with the Akt inhibitor MK2206-2HCl restored antigen presentation in Parkin-deficient tumors. Analysis of data from patients with clear cell renal cell carcinoma indicated that Parkin expression was downregulated in tumors and that low expression correlated with reduced overall survival. Furthermore, low Parkin expression correlated with reduced patient response to immunotherapy. Overall, these results identify a role for Parkin deficiency in promoting tumor immune evasion that may explain the poor prognosis associated with loss of Parkin across multiple types of cancer. SIGNIFICANCE: Parkin prevents immune evasion by regulating tumor antigen processing and presentation through the PTEN/Akt network, which has important implications for immunotherapy treatments in patients with Parkin-deficient tumors.

Evaluation of the cumulative Cherenkov converted dose on TSET patients with multiple Cherenkov cameras.

Cherenkov images can be used for the quality assurance of dose homogeneity in total skin electron therapy (TSET). For the dose mapping purpose, this study reconstructed the patient model from 3D scans using registration algorithms and computer animation techniques. The Cherenkov light emission of the patient's surface was extracted from multi-view Cherenkov images, converted into dose distribution, and projected onto the patient's 3D model, allowing for dose cumulation and evaluation. The projected result from multiple Cherenkov cameras provides additional information about Cherenkov emission on the sides of the patients, which improves the agreement between the Cherenkov converted dose and the OSLD measurements.

Efficient Synergistic Antibacterial Activity of α-MSH Using Chitosan-Based Versatile Nanoconjugates.

The application of antimicrobial peptides has emerged as an alternative therapeutic tool to encounter against multidrug resistance of different pathogenic organisms. α-Melanocyte stimulating hormone (α-MSH), an endogenous neuropeptide, is found to be efficient in eradicating infection of various kinds of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). However, the chemical stability and efficient delivery of these biopharmaceuticals (i.e., α-MSH) to bacterial cells with a significant antibacterial effect remains a key challenge. To address this issue, we have developed a chitosan-cholesterol polymer using a single-step, one-pot, and simple chemical conjugation technique, where α-MSH is loaded with a significantly high amount (37.7%), and the final product is obtained as chitosan-cholesterol α-MSH polymer-drug nanoconjugates. A staphylococcal growth inhibition experiment was performed using chitosan-cholesterol α-MSH and individual controls. α-MSH and chitosan-cholesterol both show bacterial growth inhibition by a magnitude of 50 and 79%, respectively. The killing efficiency of polymer-drug nanoconjugates was very drastic, and almost no bacterial colony was observed (∼100% inhibition) after overnight incubation. Phenotypic alternation was observed in the presence of α-MSH causing changes in the cell structure and shape, indicating stress on Staphylococcus aureus. As a further consequence, vigorous cell lysis with concomitant release of the cellular material in the nearby medium was observed after treatment of chitosan-cholesterol α-MSH nanoconjugates. This vigorous lysis of the cell structure is associated with extensive aggregation of the bacterial cells evident in scanning electron microscopy (SEM). The dose-response experiment was performed with various concentrations of chitosan-cholesterol α-MSH nanoconjugates to decipher the degree of the bactericidal effect. The concentration of α-MSH as low as 1 pM also shows significant inhibition of bacterial growth (∼40% growth inhibition) of Staphylococcus aureus. Despite playing an important role in inhibiting bacterial growth, our investigation on hemolytic assay shows that chitosan-cholesterol α-MSH is significantly nontoxic at a wide range of concentrations. In a nutshell, our analysis demonstrated novel antimicrobial activity of nanoparticle-conjugated α-MSH, which could be used as future therapeutics against multidrug-resistant Staphylococcus aureus and other types of bacterial cells.

Framework for Quality Assurance of Ultrahigh Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps.

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials.

Salvage radiotherapy for relapsed/refractory non-Hodgkin lymphoma following CD19 chimeric antigen receptor T-cell (CART) therapy.

Background and purpose: CD19-targeting chimeric antigen receptor T-cell (CART) therapy is a promising treatment for relapsed/refractory non-Hodgkin lymphoma, but most patients experience post-CART progression. We describe our institutional experience of salvage radiotherapy (SRT) in this setting. Materials and methods: Of 94 patients who received CART therapy from 2018 to 2020, 21 received SRT for post-CART progression. Patients were divided into two groups: locoregional disease (n = 9 [43 %], all disease encompassable within an RT field) and advanced disease (n = 12 [57 %]). Patterns of failure, progression-free survival (PFS), overall survival (OS), and toxicity were assessed. Results: Median time from CART infusion to SRT was 4.0 months (range, 0.6-11.5 months). In the locoregional disease group, 8/9 patients (89 %) were treated with comprehensive SRT to a median dose of 37.5 Gy in a median of 15 fractions. In the advanced disease group, all patients (n = 12) were treated with focal SRT to a median dose of 20.8 Gy in a median of 5 fractions. Median follow-up post-SRT was 15.2 months. In-field response was observed in 8/9 (89 %) in the locoregional disease and 8/9 (89 %) evaluable patients in the advanced disease groups. 17/18 evaluable patients (94 %) patients experienced post-SRT progression, all with a distant component. Median OS was 7.4 months; 21 months for locoregional disease versus 2.4 months for advanced disease (p = 0.0002). Median PFS was 1.1 month, and similarly poor regardless of group. No grade ≥ 3 toxicities occurred. Conclusions: SRT post-CART therapy appears safe with encouraging in-field response but high rates of out-of-field progression, even for those presenting with locoregional disease, highlighting the need for integration of novel systemic agents.

Evaluating patterns of care for early-stage low-grade follicular lymphoma in the rituximab era.

Radiotherapy (RT) utilization for early-stage, low-grade follicular lymphoma (FL) is low despite treatment guideline recommendations. We compare treatment trends for early-stage FL in the era of involved-site RT and rituximab. We identified 11,645 patients in the National Cancer Database (NCDB) with stage I-II, grade 1-2 nodal or extranodal FL diagnosed 2011-2017, with median follow-up of 44 months. From 2011 to 2017, RT utilization rates decreased from 33.4% to 22.4%, observation decreased from 65.3% to 49.7%, chemoimmunotherapy increased from 0.5% to 15.0%, immuno-monotherapy increased from 0.6% to 10.2%, and RT + systemic therapy increased from 0.6% to 2.5%. RT utilization remains low in the involved-site RT and rituximab era.

Proton Radiation Therapy After Chemotherapy in the Management of Aggressive Mediastinal Non-Hodgkin Lymphomas: A Particle Therapy Cooperative Group Lymphoma Subcommittee Collaboration.

Purpose: Combined modality therapy with multiagent chemotherapy and radiation therapy is a standard treatment option for aggressive mediastinal non-Hodgkin lymphomas (AMNHLs); however, concerns regarding acute and late radiation toxicities have fueled an effort to use systemic therapy alone. The use of proton therapy (PT) is a promising treatment option, but there are still limited data regarding clinical outcomes with this treatment modality. In this Particle Therapy Cooperative Group lymphoma subcommittee collaboration, we report outcomes of patients with AMNHL treated with pencil-beam scanning PT or double-scatter PT after chemotherapy. Methods and Materials: This was a multi-institutional retrospective observational cohort study of patients with AMNHL treated with PT following chemotherapy between 2011 and 2021. Progression-free survival (PFS), local recurrence-free survival (LRFS), and overall survival (OS) rates were estimated with the Kaplan-Meier method. PT toxicity was graded by the Common Terminology Criteria for Adverse Events version 5.0. A 2-tailed paired t test was used for dosimetric comparisons. Results: Twenty-nine patients were identified. With a median follow-up time of 4.2 years (range, 0.2-8.9 years), the estimated 5-year PFS for all patients was 93%, 5-year LRFS was 96%, and estimated 5-year OS was 87%. Maximum acute grade 1 (G1) toxicities occurred in 18 patients, and 7 patients had maximum G2 toxicities. No G3+ radiation-related toxicities were observed. Average mean lung dose and lung V20 Gy were lower for patients treated with pencil-beam scanning PT compared with double-scatter PT (P = .016 and .006, respectively), while patients with lower mediastinal disease had higher doses for all evaluated dosimetric heart parameters. Conclusions: PT after chemotherapy for patients with AMNHL resulted in excellent outcomes with respect to 5-year PFS, LRFS, and OS without high-grade toxicities. Future work with larger sample sizes is warranted to further elucidate the role of PT in the treatment of AMNHL.

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply.

Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results: Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 µm vasculature spacing and 18.9 µM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion: We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments.

Radiation Therapy for Relapsed or Refractory Diffuse Large B-Cell Lymphoma: What Is the Right Regimen for Palliation?

Purpose: To report objective response rates (ORR), time to local failure (TTLF), and overall survival (OS) among patients with relapsed or refractory diffuse large B-cell lymphoma after salvage- or palliative-intent radiation therapy (RT) and to investigate whether outcomes differed with conventional versus hypofractionated (≥2.5 Gy/fraction) RT. Methods and Materials: A single-institution observational cohort study was performed for patients who completed a course of RT for relapsed or refractory diffuse large B-cell lymphoma between January 1, 2008, and April 1, 2020. Predictors of ORR, TTLF, and OS were calculated using univariable and multivariable regression models. The Kaplan-Meier method was used to estimate TTLF and OS, and log-rank analysis was used to compare outcomes. Equivalent dose in 2 Gy fractions (EQD2) was calculated using an α/ß of 10. Results: One-hundred and sixty-nine patients were treated with 205 RT courses (73 [36%] salvage, 132 [64%] palliative), and hypofractionated RT was used in 100 RT courses (49%). Median RT dose was 30 Gy (range, 8-60 Gy). ORR was 60% for the total cohort (53% and 69% for palliative and salvage cohorts, respectively). Over a median follow-up time of 4 months, median OS in all patients was 5 months (3 and 22 months for palliative and salvage cohorts, respectively). No statistically significant differences in ORR, TTLF, and OS were observed with hypofractionation compared with conventional fractionation. EQD2 ≥35 Gy was associated with improved ORR (odds ratio, 3.79 [1.19-12.03]; P = .024) and prolonged TTLF (0.39 [0.18-0.87]; P = .022), while double-hit receptor status (8.18 [1.08-62.05]; P = .042), cell of origin (3.87 [1.17-8.74]; P = .0012), and bulky disease (≥7.5 cm; 2.12 [1.18-3.81]; P = .012) were associated with inferior TTLF. In the palliative-only cohort, a low-dose regimen of 8 Gy in 2 fractions was associated with similar ORR compared with other fractionation schema but trended towards inferior TTLF (P = .36). Conclusions: Hypofractionation is not associated with differences in disease outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma, while higher RT dose (EQD2 ≥35 Gy) may improve ORR and TTLF. Future work is warranted to elucidate the ideal dose and fractionation schema for such patients who will likely also undergo novel systemic agents and cellular therapies.

Shining a FLASHlight on Ultrahigh Dose-Rate Radiation and Possible Late Toxicity.

A recent study reported results from a clinical trial in cats and from experiments in mini-pigs in which a single dose of radiotherapy was delivered at ultrahigh dose rates (FLASH). There was acceptable acute toxicity; however, some animals suffered severe late toxicity, raising caution in the design of future trials. See related article by Rohrer Bley et al., p. 3814.

Low-Dose Total Body Irradiation Added to Fludarabine and Busulfan Reduced-Intensity Conditioning Reduces Graft Failure in Patients with Myelofibrosis.

Allogeneic hematopoietic cell transplantation (alloHCT) is indicated for patients with intermediate-risk or high-risk myelofibrosis (MF) and remains the sole potential cure. Reduced-intensity conditioning (RIC) is commonly used because of older patient age, comorbidities, and a high incidence of transplantation-related mortality. Patients with MF are at increased risk of graft failure (GF), which is more common with RIC regimens, and is associated with shortened overall survival (OS). Owing to the high rate of GF with conventional fludarabine (Flu) and busulfan (Bu) RIC, we added low-dose total body irradiation (TBI; 200 cGy) for patients with MF. We retrospectively compared alloHCT outcomes in adult patients with MF who received RIC with Flu/Bu/TBI and those who received RIC with Flu/Bu. The primary endpoint was the incidence of GF. Secondary endpoints included time to engraftment, acute and chronic graft-versus-host disease (GVHD), hepatic sinusoidal obstruction syndrome (SOS), nonrelapse mortality, overall response rate, progression-free survival, and OS. Of 33 patients who underwent alloHCT, 8 received Flu/Bu RIC and 25 received Flu/Bu/TBI RIC. GF occurred in 50% of the Flu/Bu recipients (all secondary GF) and in 4% of the Flu/Bu/TBI recipients (1 case of primary GF; relative risk, .08; 95% confidence interval [CI], .01 to .62; P = .0016). GF incidence was similar with related or unrelated donors and in patients who did and did not receive Janus-associated kinase inhibitors prior to alloHCT. Molecular remission and donor chimerism ≥99% were significantly more common with Flu/Bu/TBI. No significant differences in acute GVHD, chronic GVHD, or time to engraftment were observed. SOS occurred in none of the 8 patients who received Flu/Bu and in 6 of the 25 patients who received Flu/Bu/TBI, but this difference did not reach statistical significance. Progression or relapse at 1 year was less common with Flu/Bu/TBI (0% versus 63%; P < .001). The median OS was 49 months for Flu/Bu/TBI recipients and 30.8 months for Flu/Bu recipients (hazard ratio, .98; 95% CI, .33 to 2.88; P = .97). Flu/Bu/TBI resulted in a significant reduction in GF and a significant improvement in the frequency of molecular remission and full donor chimerism compared with Flu/Bu. The addition of low-dose TBI to Flu/Bu successfully mitigates against GF in patients with MF without increased rates of complications.

Moderate Colitis Not Requiring Intravenous Steroids Is Associated with Improved Survival in Stage IV Melanoma after Anti-CTLA4 Monotherapy, But Not Combination Therapy.

BACKGROUND: For patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making. MATERIALS AND METHODS: Patients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS). RESULTS: In total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS. CONCLUSION: This single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.

Transient expansion and myofibroblast conversion of adipogenic lineage precursors mediate bone marrow repair after radiation.

Radiation causes a collapse of bone marrow cells and elimination of microvasculature. To understand how bone marrow recovers after radiation, we focused on mesenchymal lineage cells that provide a supportive microenvironment for hematopoiesis and angiogenesis in bone. We recently discovered a nonproliferative subpopulation of marrow adipogenic lineage precursors (MALPs) that express adipogenic markers with no lipid accumulation. Single-cell transcriptomic analysis revealed that MALPs acquire proliferation and myofibroblast features shortly after radiation. Using an adipocyte-specific Adipoq-Cre, we validated that MALPs rapidly and transiently expanded at day 3 after radiation, coinciding with marrow vessel dilation and diminished marrow cellularity. Concurrently, MALPs lost most of their cell processes, became more elongated, and highly expressed myofibroblast-related genes. Radiation activated mTOR signaling in MALPs that is essential for their myofibroblast conversion and subsequent bone marrow recovery at day 14. Ablation of MALPs blocked the recovery of bone marrow vasculature and cellularity, including hematopoietic stem and progenitors. Moreover, VEGFa deficiency in MALPs delayed bone marrow recovery after radiation. Taken together, our research demonstrates a critical role of MALPs in mediating bone marrow repair after radiation injury and sheds light on a cellular target for treating marrow suppression after radiotherapy.

Study of epidemiological behaviour of malaria and its control in the Purulia district of West Bengal, India (2016-2020).

Purulia is a malaria-prone district in West Bengal, India, with approximately half of the blocks defined as malaria endemic. We analyzed the malaria case in each block of the Purulia district from January 1, 2016, to December 31, 2020. As per the API, 20 blocks of Purulia were assigned to four different categories (0-3) and mapped using ArcGIS software. An exponential decay model was fitted to forecast the trend of malaria cases for each block of Purulia (2021-2025). There was a sharp decrease in total malaria cases and API from 2016 to 2020 due to the mass distribution of LLINs. The majority of cases (72.63%) were found in ≥ 15-year age group. Males were more prone to malaria (60.09%). Malaria was highly prevalent among Scheduled Tribes (48.44%). Six blocks were reported in Category 3 (high risk) and none in Category 0 (no risk) in 2016, while no blocks were determined to be in Category 3, and three blocks were in Category 0 in 2020. The exponential decay model prediction is oriented towards gaining malaria-free status in thirteen blocks of Purulia by 2025. This study will incite the government to uphold and strengthen the current efforts to meet the malaria elimination goals.

Kinetics of Nanomedicine in Tumor Spheroid as an In Vitro Model System for Efficient Tumor-Targeted Drug Delivery With Insights From Mathematical Models.

Numerous strategies have been developed to treat cancer conventionally. Most importantly, chemotherapy shows its huge promise as a better treatment modality over others. Nonetheless, the very complex behavior of the tumor microenvironment frequently impedes successful drug delivery to the tumor sites that further demands very urgent and effective distribution mechanisms of anticancer drugs specifically to the tumor sites. Hence, targeted drug delivery to tumor sites has become a major challenge to the scientific community for cancer therapy by assuring drug effects to selective tumor tissue and overcoming undesired toxic side effects to the normal tissues. The application of nanotechnology to the drug delivery system pays heed to the design of nanomedicine for specific cell distribution. Aiming to limit the use of traditional strategies, the adequacy of drug-loaded nanocarriers (i.e., nanomedicine) proves worthwhile. After systemic blood circulation, a typical nanomedicine follows three levels of disposition to tumor cells in order to exhibit efficient pharmacological effects induced by the drug candidates residing within it. As a result, nanomedicine propounds the assurance towards the improved bioavailability of anticancer drug candidates, increased dose responses, and enhanced targeted efficiency towards delivery and distribution of effective therapeutic concentration, limiting toxic concentration. These aspects emanate the proficiency of drug delivery mechanisms. Understanding the potential tumor targeting barriers and limiting conditions for nanomedicine extravasation, tumor penetration, and final accumulation of the anticancer drug to tumor mass, experiments with in vivo animal models for nanomedicine screening are a key step before it reaches clinical translation. Although the study with animals is undoubtedly valuable, it has many associated ethical issues. Moreover, individual experiments are very expensive and take a longer time to conclude. To overcome these issues, nowadays, multicellular tumor spheroids are considered a promising in vitro model system that proposes better replication of in vivo tumor properties for the future development of new therapeutics. In this review, we will discuss how tumor spheroids could be used as an in vitro model system to screen nanomedicine used in targeted drug delivery, aiming for better therapeutic benefits. In addition, the recent proliferation of mathematical modeling approaches gives profound insight into the underlying physical principles and produces quantitative predictions. The hierarchical tumor structure is already well decorous to be treated mathematically. To study targeted drug delivery, mathematical modeling of tumor architecture, its growth, and the concentration gradient of oxygen are the points of prime focus. Not only are the quantitative models circumscribed to the spheroid, but also the role of modeling for the nanoparticle is equally inevitable. Abundant mathematical models have been set in motion for more elaborative and meticulous designing of nanomedicine, addressing the question regarding the objective of nanoparticle delivery to increase the concentration and the augmentative exposure of the therapeutic drug molecule to the core. Thus, to diffuse the dichotomy among the chemistry involved, biological data, and the underlying physics, the mathematical models play an indispensable role in assisting the experimentalist with further evaluation by providing the admissible quantitative approach that can be validated. This review will provide an overview of the targeted drug delivery mechanism for spheroid, using nanomedicine as an advantageous tool.

The Safety of Bridging Radiation with Anti-BCMA CAR T-Cell Therapy for Multiple Myeloma.

PURPOSE: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells (CART-BCMA) are a promising treatment for relapsed/refractory multiple myeloma (r/rMM). We evaluated the safety and feasibility of bridging radiation (RT) in subjects treated on a phase I trial of CART-BCMA. EXPERIMENTAL DESIGN: Twenty-five r/rMM subjects were treated in three cohorts with two doses of CART-BCMA cells ± cyclophosphamide. We retrospectively analyzed toxicity, response, and CART manufacturing data based on RT receipt. RESULTS: Thirteen subjects received no RT <1 year before CART infusion (Group A). Eight subjects received RT <1 year before CART infusion (Group B) with median time from RT to apheresis of 114 days (range 40-301). Four subjects received bridging-RT (Group C) with a median dose of 22 Gy and time from RT to infusion of 25 days (range 18-35). Group C had qualitatively lower rates of grade 4 (G4) hematologic toxicities (25%) versus A (61.5%) and B (62.5%). G3-4 neurotoxicity occurred in 7.7%, 25%, and 25% in Group A, B, and C, respectively. G3-4 cytokine release syndrome was observed in 38.5%, 25%, and 25% in Group A, B, and C, respectively. Partial response or better was observed in 54%, 38%, and 50% of Group A, B, and C, respectively. RT administered <1 year (P = 0.002) and <100 days (P = 0.069) before apheresis was associated with lower in vitro proliferation during manufacturing; however, in vivo CART-BCMA expansion appeared similar across groups. CONCLUSIONS: Bridging-RT appeared safe and feasible with CART-BCMA therapy in our r/rMM patients, though larger future studies are needed to draw definitive conclusions.

Comparison of FLASH Proton Entrance and the Spread-Out Bragg Peak Dose Regions in the Sparing of Mouse Intestinal Crypts and in a Pancreatic Tumor Model.

Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8-10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 ± 8.3 Gy/s or 0.82 ± 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 ± 15.2 Gy/s and 0.83 ± 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities.