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Patients are very much concerned nowadays about the replacement of their missing teeth. Missing anterior teeth are a serious concern for patients, be it an aesthetic concern or functional loss. Aesthetics is the harmony between the teeth and the entire stomatognathic system. Aesthetic is the art that the dentist must procure, with a subtle touch of artistry, appreciation, and scientific knowledge, touch to recreate the beauty of a smile that suits the face and the personality of an individual. Beauty is in the eye of the beholder hence beauty is perspective. Science and dental treatment have progressed over the years, bringing us various options from removable partial dentures to fixed partial dentures and implants. Treatment options are delineated based on the patients concern as well as anatomic, functional, and scientific norms. Every treatment being fixed or removable has its own merits and demerits. An appropriate treatment plan should look into not only the aesthetic needs of the patient but also try to restore and maintain the harmony of the entire orofacial complex. Anterior teeth replacement can be done using a short-span cantilever bridge, as it is conservative and has a significant survival rate. Conventional cantilever fixed partial dentures have a survival rate of 82% over 10 years [1]. Maryland bridge is amongst other options which necessitate minimal tooth reduction with optimum bonding using adhesive cement. &nbsp

Mucormycosis is an opportunistic fungal infection that invades rapidly and is usually seen in the immunocompromisedpatients.Rhinocerebral and pulmonary are the main two forms.Rhinocerebral form starts in the maxillary antrum and invades rapidly to causenecrotizing ulceration of palate with a blackish slough andsubsequentexposure of bone.Initial finding that is usually found is sinus opening or palatal perforation and subsequent mobility of teeth. Surgical resection of the necrosed area results in a defect that may vary from a small opening to extensive defect.Sothe prosthodontic management becomes important to aid the patient with basic functions that is mastication , speech and esthetics.This case report presents a case of the prosthodontic management of the acquired maxillary defect that occurred secondary to mucormycosis in a known diabetic male patient. &nbsp

The advent of Magnetic Resonance Imaging (MRI) and Cone Beam Computed Tomography (CBCT) have made the evaluation of the temporomandibular joint (TMJ) far more definitive than the previous X-ray technologies. However, there is a large gap between what can be accomplished diagnostically in a clinical practice setting compared to utilizing these sophisticated imaging technologies. While the history and clinical examination procedures reveal important information, too often they are inadequate to arrive at even a tentative diagnosis of TMJ status. JVA tool is helpful for diagnosing joint pathology or abnormality by detecting the vibration between the joint surfaces. It is useful for diagnosis and educating patients during treatment.

3D printing also called additive manufacturing (AM) has rapidly evolved over the last few decades due to its various advantages over traditional fabrication methods. Recent advancement in 3D printing is 4D/four-dimensional printing. It includes fourth dimension i.e time. Basically, 4D printing adds time to the 3D printing and this addition provides reconfiguration to a printed object, that is, 4D printed structure will reconfigure itself to the pre-determined shape with time on exposure to various stimuli. It is a recent evolving technology, rapidly emerging in various fields like medical, engineering, automobile industry, chemistry, material science, basic sciences, computer science etc.[1] In Dentistry ,moving on from traditional fabrication methods to 3D printing and now to 4D printing would be a boon to various treatment procedures and so to the prognosis as well. The objective of 4D printing is to fabricate functional objects in contrast to 3D printing techniques which produce static objects. The main focus of this article is to review basic aspects of 4D printing technology and its application in dentistry.

One of the areas of contemporary research that is quickly acquiring worldwide recognition as a result of digitalization is artificial intelligence (AI). Medical and dental field are also not left behind in this digitization era. They are using AI to reduce the work load and to improve clinical diagnosis so that the clinician can provide better treatment planning and predict the prognosis of a disease. AI is used in the field of dentistry and can be applied to all its specialities including prosthodontics. In prosthodontics they are helpful in designing the prosthesis, implant planning and placement and in fabrication of maxillofacial prostheses.

T cells in the tumor micro-environment require TCR/MHC engagement and co-stimulatory receptor engagement to achieve optimal activation. Solid tumor cells lack expression of CD28 ligands, so we hypothesized that activation of CD28 signaling at the T cell/tumor cell interface could enhance anti-tumor activity. We developed a CD28 bispecific platform that allows for the rapid generation of tumor-associated antigen (TAA) x CD28 bispecific antibodies that conditionally provide CD28 costimulation only in the presence of TAA and TCR engagement. Here, we present results for a set of bispecific antibodies with broad applicability across a range of solid tumors, including CEACAM5 x CD28, Trop-2 x CD28, STEAP1 x CD28, and mesothelin x CD28. We developed optimized CD28 scFv and Fabs that cover a range of affinities and are only agonistic in the context of TCR engagement. A matrix of bispecifics pairing these CD28 binders with CEACAM5, Trop-2, STEAP1, and mesothelin antibodies of varying affinities and epitopes were generated using Xencor’s XmAb® bispecific antibody platform. Activities of these bispecifics were assessed in vitro by measuring T cell proliferation, cytokine production, and cytotoxicity in co-cultures of human cancer cell lines mixed with primary human T cells. CEACAM5 x CD28, Trop-2 x CD28, STEAP1 x CD28, and mesothelin x CD28 bispecifics enhanced T cell degranulation, cytokine secretion, and cancer cell cytotoxicity only in concert with TCR engagement. IHC was used to compare TAA expression on cancer cell lines versus that found on cancer tissues, allowing categorization of cell lines as high density (tumor surrogate) or low density (normal tissue surrogate). CD28 bispecifics were identified with selective potency on high versus low expressing cell lines, suggesting a favorable therapeutic index. CD28 bispecific antibodies co-targeting CEACAM5, Trop-2, STEAP1, and mesothelin show promising activity and warrant further development across a range of solid tumors. Citation Format: Matthew A. Dragovich, Viralkumar Davra, Matthew S. Faber, Yoon Kyung Kim, Alex Nisthal, Veronica G. Zeng, Jonathan Jacinto, Juan E. Diaz, Thuy Truong, Jing Qi, Kendra N. Avery, Rumana Rashid, Sung-Hyung Lee, Seung Y. Chu, Christine Bonzon, Ruschelle Love, Matthew J. Bernett, James A. Ernst, Rena Bahjat, Norman J. Barlow, John R. Desjarlais, Michael Hedvat, Gregory L. Moore. Tumor-specific CD28 costimulatory bispecific antibodies enhance T cell activation in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2983.

Claudin 18.2 (CLDN18.2) is a member of the claudin family of proteins that are involved in the formation of tight junctions in epithelia and endothelia. In normal tissue, CLDN18.2 is expressed exclusively on gastric epithelial cells. CLDN18.2 expression is maintained during malignant transformation of gastric epithelia. In addition, it is aberrantly expressed in other tumor types, including esophageal, pancreatic, and lung adenocarcinomas. Thus, CLDN18.2 is considered to be an attractive tumor target antigen for antibody-based cancer immunotherapy. ASP2138 is an immunoglobulin G (IgG)-based, asymmetric 2+1 format, T-cell bispecific antibody comprising bivalent humanized anti-CLDN18.2 antigen-binding fragments and a monovalent anti-CD3 single-chain variable fragment. CD3 is a surface protein complex expressed on all T-cell populations and its clustering causes T-cell activation. Therefore, CD3 bispecific antibodies allow for simultaneous engagement with both CD3 and a tumor-associated antigen (TAA), resulting in retargeting of cytotoxic T cells specifically against TAA-positive tumor cells in a human leukocyte antigen-independent manner. ASP2138 is in development for the treatment of patients with CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma or pancreatic adenocarcinoma, and is being evaluated in an ongoing phase 1/1b clinical trial (NCT05365581). In this study, ASP2138 demonstrated selective binding to CLDN18.2 and CD3 without binding to other homologs and isoforms of CLDN18.2. Cytotoxicity and T-cell activation of ASP2138 were assessed using CLDN18.2-expressing tumor cells in combination with human peripheral blood mononuclear cells (PBMCs) as effector cells in a redirected T-cell cytotoxicity assay in vitro. ASP2138 showed cytotoxicity against CLDN18.2-expressing gastric or pancreatic cancer cells and increased interferon-gamma production and expression of T-cell activation markers. The cytotoxic activities were dependent on the effector cell to target cell ratio and CLDN18.2 expression on tumor cells. ASP2138 exhibited an antitumor effect on human CLDN18.2-expressing gastric cancer in a human PBMC-engrafted NOG mouse model in vivo. In summary, ASP2138 is expected to show a clinical effect through cytotoxicity against CLDN18.2-expressing tumor cells by T-cell activation that results from selective binding to CLDN18.2 and CD3. Citation Format: Taisuke Nakazawa, Hiroaki Tanaka, Aya Kikuchi, Rumana Rashid, Kendra N. Avery, Jing Qi, Alex Nisthal, Masashi Shimazaki, Kenna Shirasuna. ASP2138, a novel 2+1 format, claudin 18.2 x CD3 bispecific antibody, demonstrates selectivity and activity in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2962.

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

Under proteotoxic stress, some cells survive whereas others die. The mechanisms governing this heterogeneity in cell fate remain unknown. Here we report that condensation and phase transition of heat-shock factor 1 (HSF1), a transcriptional regulator of chaperones1,2, is integral to cell-fate decisions underlying survival or death. During stress, HSF1 drives chaperone expression but also accumulates separately in nuclear stress bodies called foci3-6. Foci formation has been regarded as a marker of cells actively upregulating chaperones3,6-10. Using multiplexed tissue imaging, we observed HSF1 foci in human tumours. Paradoxically, their presence inversely correlated with chaperone expression. By live-cell microscopy and single-cell analysis, we found that foci dissolution rather than formation promoted HSF1 activity and cell survival. During prolonged stress, the biophysical properties of HSF1 foci changed; small, fluid condensates enlarged into indissoluble gel-like arrangements with immobilized HSF1. Chaperone gene induction was reduced in such cells, which were prone to apoptosis. Quantitative analysis suggests that survival under stress results from competition between concurrent but opposing mechanisms. Foci may serve as sensors that tune cytoprotective responses, balancing rapid transient responses and irreversible outcomes.

Multiplexed tissue imaging facilitates the diagnosis and understanding of complex disease traits. However, the analysis of such digital images heavily relies on the experience of anatomical pathologists for the review, annotation, and description of tissue features. In addition, the wider use of data from tissue atlases in basic and translational research and in classrooms would benefit from software that facilitates the easy visualization and sharing of the images and the results of their analyses. In this Perspective, we describe the ecosystem of software available for the analysis of tissue images and discuss the need for interactive online guides that help histopathologists make complex images comprehensible to non-specialists. We illustrate this idea via a software interface (Minerva), accessible via web browsers, that integrates multi-omic and tissue-atlas features. We argue that such interactive narrative guides can effectively disseminate digital histology data and aid their interpretation.

In a tropical country like Bangladesh where the climatic condition favors the growth of Aedes mosquito vectors, the success of dengue prevention depends largely on the proper identification and controlling of the socio-demographic and lifestyle-related risk factors. A case-control study including 150 cases and 150 controls were conducted aimed to explore the potential risk and protective factors and their association with dengue virus infection in the Chattogram district of Bangladesh. Cases were confirmed for dengue patients admitted in Chattogram medical college hospital and Bangladesh institute of tropical and infectious diseases during August and September 2019. Whereas, controls were non-dengue patients admitted in other departments of the same hospitals through gender age and location matching. The questionnaire data were collected through telephone-based interviews which included information regarding general demography, daily life activities, housing with its surroundings status. Chi-square and binary logistic regression were performed for identifying potential risk factors and their association with the occurrences of dengue fever.The study found that travel history to the high incidence area, the place of staying most of the time, living in 21 to 40 years old houses, and the temporary residence of the city were statistically significant risk factors for getting the dengue infection. On contrary, Quality of indoor daylight, ventilation, bus stand/garage, stagnant water, and any construction site around 250 meters of the house did not show significant association with dengue fever.

The absence of population-based seroprevalence estimates in Bangladesh have impeded efforts to understand the relatively low reported mortality and incidence rates of SARS-CoV-2 in this country. We report findings of a representative serosurvey of the Sitakunda subdistrict in the Chattogram division of Bangladesh before a nationwide lockdown in April 2021. After adjusting for age, sex, household clustering and test performance using a Bayesian modeling approach, we estimate the seroprevalence of SARS-CoV-2 to have been 63.1% (56.2-60.8%) in Sitakunda during this period. These results illustrate that going into the national lockdown in April 2021, the majority of this population had already been infected despite a relatively low incidence of medically attended COVID-19.

How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioma. We show that microglia are the predominant source of CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, and increased adenosine, and is linked to hypoxia. Glioblastomas enriched for CD73 exhibit inflammatory microenvironments, suggesting that purinergic signaling regulates immune adaptation. Spatially-resolved single-cell analyses demonstrate a strong spatial correlation between tumor-CD73 and microglial-CD39, with proximity associated with poor outcomes. Similar spatial organization is present in pediatric high-grade gliomas including H3K27M-mutant diffuse midline glioma. These data reveal that purinergic signaling in gliomas is shaped by genotype, lineage, and functional state, and that core enzymes expressed by tumor and myeloid cells are organized to promote adenosine-rich microenvironments potentially amenable to therapeutic targeting.

Multiplexed tissue imaging enables precise, spatially resolved enumeration and characterization of cell types and states in human resection specimens. A growing number of methods applicable to formalin-fixed, paraffin-embedded (FFPE) tissue sections have been described, the majority of which rely on antibodies for antigen detection and mapping. This protocol provides step-by-step procedures for confirming the selectivity and specificity of antibodies used in fluorescence-based tissue imaging and for the construction and validation of antibody panels. Although the protocol is implemented using tissue-based cyclic immunofluorescence (t-CyCIF) as an imaging platform, these antibody-testing methods are broadly applicable. We demonstrate assembly of a 16-antibody panel for enumerating and localizing T cells and B cells, macrophages, and cells expressing immune checkpoint regulators. The protocol is accessible to individuals with experience in microscopy and immunofluorescence; some experience in computation is required for data analysis. A typical 30-antibody dataset for 20 FFPE slides can be generated within 2 weeks.

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi’s response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma., BET-bromodomain inhibitors could be used to treat medulloblastoma tumors with Myc amplifications. Here, the authors show that both the response and resistance to BET inhibitors in mice is mediated by bHLH/homeobox transcription factors.

Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in the NF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibular schwannomas; however, patients also have a predisposition to development of other tumors including meningiomas, ependymomas, and peripheral, spinal, and cranial nerve schwannomas. Patients may also develop other characteristic manifestations such as ocular lesions, neuropathies, meningioangiomatosis, and glial hamartia. NF2 has a highly variable clinical course, with some patients exhibiting a severe phenotype and development of multiple tumors at an early age, while others may be nearly asymptomatic throughout their lifetime. Despite the high morbidity associated with NF2 in severe cases, management of NF2-associated lesions primarily consists of surgical resection and treatment of symptoms, and there are currently no FDA-approved systemic therapies that address the underlying biology of the syndrome. Refinements to the diagnostic criteria of NF2 have been proposed over time due to increasing understanding of clinical and molecular data. Large-population studies have demonstrated that some features such as the development of gliomas and neurofibromas, currently included as diagnostic criteria, may require further clarification and modification. Meanwhile, burgeoning insights into the molecular biology of NF2 have shed light on the etiology and highly variable severity of the disease and suggested numerous putative molecular targets for therapeutic intervention. Here, we review the clinicopathologic features of NF2, current understanding of the molecular biology of NF2, particularly with regard to central nervous system lesions, ongoing therapeutic studies, and avenues for further research.

not available Bangladesh J Medicine July 2022; 33(1) : 126-127

The IL2Rβ/γc binding human cytokines IL2 and IL15 aid in the activation, proliferation, and survival of T and NK cells, and their therapeutic potential has been well established in animal models and human trials. However, therapeutic approaches utilizing these cytokines have suffered from low tolerability, fast clearance, and limited therapeutic window due to extensive activity on peripheral lymphocytes. Conversely, higher drug concentration and prolonged exposure are desirable to allow lymphocyte activation and proliferation at the tumor site, but this can be difficult to achieve due to dose-limiting toxicities associated with this axis. IL15 functions as a stabilized heterodimeric complex with membrane-bound IL15Rα on the surface of monocytes and DCs, which is presented in trans to lymphocytes expressing IL2Rβ/γc. We hypothesized that we could selectively target tumor-reactive TILs by combining a reduced potency IL15/IL15Rα heterocomplex with an immune checkpoint(CP)-targeting arm to bias binding and activation to CP-positive TILs, potentially improving therapeutic index. Lymphocyte activation gene 3 (LAG3) was chosen as the CP targeting-arm due to its frequent co-expression with PD1, bias to CD8+ T cells, ability to easily combine with anti-PD1 agents, and recent promising results with anti-LAG3 agents in the clinic. First, potency-reduced IL15/IL15Rα were created by engineering amino acid substitutions in IL15 - at the IL2Rβ/γc interface - that reduced in vitro potency by at least 1000-fold. We then designed LAG3 x IL15 fusion proteins containing single-chain IL15/IL15Rα and LAG3-targeting arms attached to a heterodimeric-Fc region, relying on targeting avidity to recover potency on LAG3+ cells. In vitro proliferation of lymphocytes in human PBMCs, stimulated with sub-optimal concentrations of anti-CD3 to induce LAG3 expression, was monitored by CFSE dilution or by counting Ki67+ cells after incubation with LAG3 x IL15 for 4 days. In vivo activity was evaluated using humanized mouse models by measuring the extent of human leukocyte expansion. Lead LAG3 x IL15 were evaluated for pharmacodynamic activity, pharmacokinetics, and tolerability in non-human primates. LAG3 x IL15 showed >500-fold selectivity compared to a non-targeted IL15 in an in vitro proliferation assay of lymphocytes stimulated for induced LAG3 expression. In vitro potency was greatest on effector memory CD8 T cells. LAG3 x IL15 were 3-fold more potent on CD8 T cells compared to CD4 T cells and had very weak activity on NK cells, consistent with minimal LAG3 expression on this population. In mouse models, treatment with LAG3 x IL15 promoted significantly increased numbers of T cells. Moreover, LAG3 x IL15 combined productively with anti-PD1 to promote additional T cell expansion. These results demonstrate that LAG3 x IL15 show a promising profile of selective IL15 delivery to TIL with minimal peripheral activity. Citation Format: Matthew J. Bernett, Suzanne Schubbert, Michael Hackett, Lukasz J. Ochyl, Lizett E. Scott, Christine Bonzon, Rumana Rashid, Kendra N. Avery, Irene W. Leung, Nicole Rodriguez, Connie Ardila, Umesh S. Muchhal, Norman J. Barlow, Rena Bahjat, John R. Desjarlais. LAG3-targeted IL15/IL15Rα-Fc (LAG3 x IL15) fusion proteins for preferential TIL expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2080.

Interleukin-18 (IL18) is a proinflammatory cytokine that modulates both innate and adaptive immune responses. After processing of the inactive precursor within monocytes and macrophages, mature IL18 can promote the expansion, survival, and cytotoxicity of T and NK cells expressing its receptor subunits IL-18Rα (IL18R1) and IL18Rβ (IL18RAP). Preclinical studies with recombinant IL18 have demonstrated anti-tumor activity in animal models, including impressive synergy with both immune checkpoint inhibitors and CAR-T therapy. However, clinical development exhibited poor pharmacokinetics and an overall lack of efficacy despite heavy dosing. IL18 participates in a negative feedback loop with a very high affinity natural inhibitor, IL18 binding protein (IL18BP), whose expression is induced by IFNγ. As IL18BP upregulation was observed in early phase clinical trials, it likely limited the efficacy of recombinant IL18. Here, we have engineered next generation IL18 cytokines that aim to improve on the poor PK of WT and contend with IL18BP induction. Prior work at Xencor demonstrated that reduced-potency IL15/IL15Rα-Fc fusion proteins exhibited superior pharmacokinetics, pharmacodynamics, and safety in non-human primates through reduction of receptor-mediated clearance. Following that principle, we generated monovalent IL18-Fc fusions upon our XmAb® heterodimeric Fc platform and introduced substitutions that could modulate IL18 stability, affinity toward the IL18 heterodimeric receptor, and affinity toward IL18BP. Initially, IL18-Fc was difficult to produce but yields improved to typical bispecific antibody levels after stabilization. An engineered disulfide bridge increased the WT thermal denaturation temperature from 45 °C to 65 °C, and demonstrated a significant improvement in serum clearance in mouse PK experiments. Variants at IL18 positions along the receptor and IL18BP interfaces were explored in vitro by measuring PD-L1 induction on KG-1 cells, with and without a high concentration of IL18BP. Recombining a select number of hits generated a potency series with variants exhibiting over a 2,000-fold reduction in PD-L1 induction potency as compared to WT IL18-Fc. Importantly, we identified variants that no longer detectably bound IL18BP, relieving natural inhibition of our engineered IL18-Fc. In vivo immune-mediated inflammation was explored in human PBMC engrafted mouse models of graft versus host disease (GvHD). We observed potency-dependent exacerbation of GvHD, with corresponding dramatic increases in the numbers and activation of T and NK cells as compared to a human PBMC only control. Analysis of serum from the study revealed up to 100-fold increases in IFNγ levels. Our engineered, reduced-potency IL18-Fc cytokines demonstrate robust inflammation activity in vivo, improved pharmacokinetics in mice, and insensitivity to IL18BP inhibition. Citation Format: Alex Nisthal, Sung-Hyung Lee, Christine Bonzon, Ruschelle Love, Kendra N. Avery, Rumana Rashid, Panida Lertkiatmongkol, Nicole Rodriguez, Hanh Nguyen, Araz Eivazi, Sher Karki, Norm Barlow, Seung Y. Chu, Greg L. Moore, John R. Desjarlais. Engineered IL18 heterodimeric Fc-fusions featuring improved stability, reduced potency, and insensitivity to IL18BP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3515.

BackgroundCorticosteroid has been used to manage inflammation caused by many diseases including respiratory viral infections. Many articles are available to support the good and bad side of this steroid use but remain inconclusive. To find some evidence about the safety of the drug, we investigated the effect of corticosteroids on the mortality of patients with respiratory viral infections including SARS-CoV-2, SARS, MERS, and Influenza.MethodWe searched articles in PubMed, Scopus, Cochrane, Medline, Google Scholar, and Web of Science records using keywords “corticosteroid” or “viral infection” or “patients” or “control study”. Mortality was the primary outcome.ResultOur selected 24 studies involving 16633 patients were pooled in our meta-analysis. Corticosteroid use and overall mortality were not significantly associated (P=0.176), but in subgroup analysis, corticosteroid use was significantly associated with lower mortality in the case of SARS (P=0.003) but was not significantly associated with mortality for Influenza (H1N1) (P=0.260) and SARS-CoV-2 (P=0.554). Further analysis using study types of SARS-CoV-2, we found that corticosteroid use was not significantly associated with mortality in the case of retrospective cohort studies (P=0.256) but was significantly associated with lower mortality in the case of randomized control trials (P=0.005). Our findings uncover how the outcome of particular drug treatment for different diseases with comparable pathogenesis may not be similar and, RCTs are sometimes required for robust outcome data.ConclusionAt the beginning of the COVID-19 pandemic, data of corticosteroid use from other viral infections along with COVID-19 observational and retrospective cohort studies created confusion of its effect, but randomized control trials showed that corticosteroid can be used to treat COVID-19 patients.

Background In 2017 hundreds of thousands of ‘Rohingya’ fled to camps for Forcefully Displaced Myanmar Nationals (FDMN) in Cox’s Bazar, Bangladesh. Objective To describe the FDMNs presenting for care at public health facilities in Bangladesh so as to understand the health problems faced by the FDMNs and the burden on these public health facilities. Methods This study combined a retrospective review of existing hospital and clinic data with prospective surveillance in government health care centres. Findings The retrospective data showed a 26% increase in the number of consultations at the Kutupalong community clinic, the primary health facility closest to the camps, from 19,567 in 2015 to 26,309 in 2019. There was a corresponding 11% increase in admissions to health facilities in the area, from 80,991 in 2017 to 91,424 in 2019. Prospective surveillance of 9,421 FDMNs seeking health care from July 2018 to December 2019 showed that 29% had an infectious disease, 20% nutritional problems, 12% pregnancy-related conditions and 7% trauma or injury. Conclusions Great uncertainty remains regarding the return of FDMN to their home country of Myanmar. The current on-going protests following the military coup adds further insecurity to the status of the Rohingya. The presence of a large migrant population relative to a smaller host community burdens the limited facilities and resources of the public health sector. Continued support by the international public health community and civil society organizations is needed.

This study investigates the impact of Foreign Direct Investment (FDI) on economic growth and examines the causality between FDI and economic growth in Bangladesh during 1972-2013. Gross Domestic Product (GDP), export performance (EXP), Foreign Direct Investment (FDI), and Gross Fixed Capital Formation (GFCF) are considered to capture the objective of the study. The study methodology includes some systematic steps. As the data used in the study is time-series in nature, the author employs unit root tests, and in this case, Augmented Dickey-Fuller (ADF) and Phillips-Perron (PP) tests are used. Then Johansen’s cointegration test, Granger causality test, regression with Newey-West Standard Error and Vector Error Correction Model (VECM) are applied. By using the ADF and PP test the study reveals that the variables of four-time series are integrated of I (1) i.e. they are stationary at first difference. Regression analysis result demonstrates that FDI has a positive effect on economic growth. The Granger Causality test discloses that there is a unidirectional relationship between FDI and economic growth. But the VECM estimation finds that in the long run FDI negatively affects economic growth.

Background Interleukin-12 (IL12) is a proinflammatory cytokine produced by activated antigen-presenting cells that induces differentiation of Th1 cells and increased proliferation and cytotoxicity of T and NK cells. Stimulation of these cells by IL12 leads to production of high levels of IFNγ. These immune-stimulating aspects of IL12 may help to establish an inflammatory tumor microenvironment critical for anti-tumor responses. Preclinical studies in mice revealed that native IL12 can dramatically shrink syngeneic tumors, however clinical studies in humans resulted in severe toxicity and a small therapeutic window, limiting response rates. Prior work at Xencor demonstrated that reduced-potency IL15/IL15Rα-Fc fusion proteins exhibited superior pharmacokinetics, pharmacodynamics, and safety in non-human primates through reduction of receptor-mediated clearance. Applying similar principles to IL12, we created IL12 heterodimeric Fc-fusions (IL12-Fc) with reduced potency to improve tolerability, slow receptor-mediated clearance, and extend half-life. Methods IL12 is a heterodimeric protein consisting of two subunits, so we engineered IL12-Fc fusions by fusing the IL12p35 subunit to one side of a heterodimeric (and inactive) Fc domain, and the IL12p40 subunit to the other side. These Fc-fusions were tuned for optimal activity by introducing amino acid substitutions at putative receptor-interface positions and screening for reductions of in vitro potency. In vitro activity was assessed on human PBMCs by measuring signaling in a STAT4 phosphorylation assay and IFNγ production in a mixed-lymphocyte reaction (MLR). In vivo anti-tumor activity was assessed by engrafting MCF-7 cells into PBMC engrafted NSG MHC class I and II double-knockout mice and by measuring tumor volume, lymphocyte activation/proliferation, and IFNγ production over time. Results IL12-Fc were produced with good yield and purity. An IL12-Fc potency series was created, and variants had up to a 10,000-fold reduction in STAT4 signaling potency and IFNγ production in an MLR assay compared to native IL12-Fc. Anti-tumor activity in the huPBMC-MCF7 model was achieved with potency-reduced IL12-Fc as a single-agent and in combination with anti-PD1, with weaker variants maintaining anti-tumor activity at higher dose levels. Analysis of peripheral lymphocytes indicated increased numbers of T and NK cells as well as activation of CD8+ T cells, as evidenced by upregulation of CD25. Increased expression of immune checkpoints including PD1 was also observed. Analysis of serum indicated up to 200-fold increases in IFNγ levels. Conclusions Combined, these data indicate that potency-reduced IL12-Fc retain strong anti-tumor activity, while potentially overcoming safety and tolerability issues related to small therapeutic index associated with recombinant native IL12 or IL12-Fc agents.

Background T cells in the tumor micro-environment require TCR/MHC engagement and co-stimulatory receptor engagement to achieve complete activation. Solid tumors often lack expression of CD28 ligands, so we hypothesized that activation of CD28 signaling could be beneficial in solid tumors. We designed tumor-associated-antigen (TAA) x CD28 bispecific antibodies that conditionally costimulate CD28 only in the presence of TAA and TCR engagement. Clinical application of this class of antibodies has potential to enhance activity of either anti-PD(L)1 antibodies or TAA x CD3 T cell engagers. Methods We designed a stability and affinity optimized anti-CD28 antibody that can be paired with TAA of choice to engage CD28 monovalently using Xencor’s XmAb 2+1 and 1+1 platforms. In vitro T cell activation with these bispecifics was measured by T cell proliferation, cytokine production, and cytotoxicity, in co-cultures of human cancer cell lines mixed with primary human CD3-stimulated T cells. In vitro activity was validated in a CMV recall assay measuring CMV+ T cell proliferation of CMV+ PBMC co-cultured with cancer cell lines ectopically treated with pp65-derived NLV-peptide. In vivo anti-tumor and T cell proliferative activity of B7H3 x CD28 bispecific antibodies were determined in tumor-bearing huPBMC-NSG mice treated simultaneously with TAA x CD3 bispecific antibody. In vivo activity of PDL1 x CD28 antibodies was determined with hCD28 KI mice inoculated with MC38 tumors expressing hPDL1-antigen. Finally, safety and tolerability of B7H3 x CD28 and PDL1 x CD28 was determined in cynomolgus monkeys. Results B7H3 x CD28 and PDL1 x CD28 antibodies enhanced T cell degranulation, cytokine secretion, and cancer cell cytotoxicity in concert with CD3 stimulation only in the presence of target antigen. B7H3 x CD28, alone or in combination with anti-PD1 antibody, enhanced proliferation of CMV+ T cells recognizing cancer cells loaded with pp65-derived NLV peptide. PDL1 x CD28 also enhanced CMV+ cell expansion but did not synergize with anti-PD1 antibody treatment. B7H3 x CD28 significantly enhanced in vivo anti-tumor activity of TAA x CD3 antibodies while also promoting greater T cell expansion. In hCD28 mice inoculated with MC38 tumors expressing hPDL1, PDL1 x CD28 antibody inhibited tumor growth greater than an anti-PDL1 antibody alone. B7H3 x CD28 and PDL1 x CD28 were well tolerated in cynomolgus monkeys. Conclusions B7H3 x CD28 and PDL1 x CD28 bispecific antibodies show promising anti-tumor activity and warrant further development.