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Utility of 211At-trastuzumab for the Treatment of Metastatic Gastric Cancer in the Liver: Evaluation of a Preclinical α-Radioimmunotherapy Approach in a Clinically-relevant Mouse Model.

February 7, 2021 By Manish Butte

Utility of 211At-trastuzumab for the Treatment of Metastatic Gastric Cancer in the Liver: Evaluation of a Preclinical α-Radioimmunotherapy Approach in a Clinically-relevant Mouse Model.

J Nucl Med. 2021 Feb 05;:

Authors: Li HK, Morokoshi Y, Kodaira S, Kusumoto T, Minegishi K, Kanda H, Nagatsu K, Hasegawa S

Abstract
A liver metastasis from a primary gastric cancer (LMGC) is relatively common and results in an extremely poor prognosis due to a lack of effective therapeutics. We here demonstrate in a clinically-relevant mouse model that an α-radioimmunotherapy (α-RIT) approach with astatine-211-labeled-trastuzumab (211At-trastuzumab) has efficacy against LMGCs that are positive for human epidermal growth factor receptor 2 (HER2). Methods: 211At was produced in a cyclotron via a 209Bi (α, 2n) 211At reaction. 211At-trastuzumab was subsequently generated using a single-step labelling method. NCI-N87 cells (HER2-positive human GC cells) carrying a luciferase gene were intrasplenically transplanted into severe combined immunodeficiency mice to generate a HER2-positive LMGC model. A bio-distribution study was then conducted through the intravenous injection of 211At-trastuzumab (1 MBq) into these LMGC xenograft mice. In parallel with this experimental therapy, PBS, intact trastuzumab or 211At-non-specific human IgG (1MBq) were injected into control groups. The therapeutic efficacy was evaluated by monitoring tumor changes by chemiluminescence imaging. Monitoring of body weights, white blood cell counts, and serum markers of tissue damage were conducted at regular intervals. Microdosimetry using a CR39 plastic detector was also performed. Results: The biodistribution analysis revealed an increased uptake of 211At-trastuzumab in the metastasized tumors that reached approximately 12% of the injected dose per gram of tissue (%ID/g) at 24 hours. In contrast, its uptake to the surrounding liver was about 4%ID/g. The LMGCs in the mouse model reduced dramatically at 1 week after the single systemic injection of 211At-trastuzumab. No recurrences were observed in six of eight mice treated with this single injection and their survival time was significantly prolonged compared to the control groups, including the animals treated with 211At-non-specific antibodies. No severe toxicities or abnormalities in terms of body weight, white blood cell number, liver function, or kidney parameters were observed in the 211At-trastuzumab group. Microdosimetric studies further revealed that 211At-trastuzumab had been delivered at an 11.5- fold higher dose to the LMGC lesions compared to the normal liver. Conclusion: α-RIT with 211At-trastuzumab has considerable potential as an effective and safe therapeutic option for LMGC.

PMID: 33547212 [PubMed – as supplied by publisher]

Rapid clinical recovery of a SARS-CoV-2 infected common variable immunodeficiency patient following the infusion of COVID-19 convalescent plasma.

February 7, 2021 By Manish Butte

Rapid clinical recovery of a SARS-CoV-2 infected common variable immunodeficiency patient following the infusion of COVID-19 convalescent plasma.

Allergy Asthma Clin Immunol. 2021 Feb 05;17(1):14

Authors: Ribeiro LC, Benites BD, Ulaf RG, Nunes TA, Costa-Lima C, Addas-Carvalho M, Proenca-Modena JL, Granja F, da Costa VA, Duarte ADSS, Zangirolami AB, Amaro EC, Mansour E, Zollner RL, Velloso LA

Abstract
BACKGROUND: Common variable immunodeficiency is the most prevalent symptomatic primary immunodeficiency in adults. Affected patients fail to mount an appropriate humoral response against community acquired infectious diseases and recent reports have provided data supporting the increased susceptibility of these patients to severe SARS-CoV-2 infections. In this context, the infusion of COVID-19 convalescent plasma could represent an effective therapeutic strategy.
CASE PRESENTATION: 25-year old woman diagnosed with common variable immunodeficiency in 2013, developed severe COVID-19 that rapidly progressed to pneumonia presenting with multiple bilateral lung opacities that were both central and peripheral and presented as ground-glass and consolidation types involving all lobes, bilaterally. As blood oxygen saturation decayed and lung abnormalities were not responsive to large spectrum antibiotics and corticosteroids, patient was placed on mechanical ventilation and compassionate-use of approved COVID-19 convalescent donor plasma was introduced. The patient presented a rapid response to the approach and mechanical ventilation could be interrupted 24 h after first dose of COVID-19 convalescent donor plasma. As a whole, the patient received four doses of 200 mL convalescent plasma during a period of 6 days. There was rapid improvement of clinical status, with interruption of supplemental oxygen therapy after 6 days and reduction of lung abnormalities as evidence by sequential computed tomography scans.
CONCLUSIONS: This is a single patient report that adds to other few reports on common variable immunodeficiency and agammaglobulinemia, suggesting that COVID-19 convalescent donor plasma could be a valuable therapeutic approach to treat patients affected by dysgammaglobulinemias and presenting severe COVID-19.

PMID: 33546745 [PubMed – as supplied by publisher]

Control of Hereditary Angioedema. Reply.

February 6, 2021 By Manish Butte

Control of Hereditary Angioedema. Reply.

N Engl J Med. 2021 02 04;384(5):e11

Authors: Fijen LM, Stroes ESG, Cohn DM

PMID: 33534989 [PubMed – indexed for MEDLINE]

Control of Hereditary Angioedema.

February 6, 2021 By Manish Butte

Control of Hereditary Angioedema.

N Engl J Med. 2021 02 04;384(5):e11

Authors: Wang C

PMID: 33534988 [PubMed – indexed for MEDLINE]

The Bloom syndrome complex senses RPA-coated single-stranded DNA to restart stalled replication forks.

February 6, 2021 By Manish Butte

The Bloom syndrome complex senses RPA-coated single-stranded DNA to restart stalled replication forks.

Nat Commun. 2021 01 26;12(1):585

Authors: Shorrocks AK, Jones SE, Tsukada K, Morrow CA, Belblidia Z, Shen J, Vendrell I, Fischer R, Kessler BM, Blackford AN

Abstract
The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1 and RMI2 to form the BTR complex, which dissolves double Holliday junctions to produce non-crossover homologous recombination (HR) products. BLM also promotes DNA-end resection, restart of stalled replication forks, and processing of ultra-fine DNA bridges in mitosis. How these activities of the BTR complex are regulated in cells is still unclear. Here, we identify multiple conserved motifs within the BTR complex that interact cooperatively with the single-stranded DNA (ssDNA)-binding protein RPA. Furthermore, we demonstrate that RPA-binding is required for stable BLM recruitment to sites of DNA replication stress and for fork restart, but not for its roles in HR or mitosis. Our findings suggest a model in which the BTR complex contains the intrinsic ability to sense levels of RPA-ssDNA at replication forks, which controls BLM recruitment and activation in response to replication stress.

PMID: 33500419 [PubMed – indexed for MEDLINE]

Patient‑derived orthotopic xenograft glioma models fail to replicate the magnetic resonance imaging features of the original patient tumor.

February 6, 2021 By Manish Butte

Patient‑derived orthotopic xenograft glioma models fail to replicate the magnetic resonance imaging features of the original patient tumor.

Oncol Rep. 2020 May;43(5):1619-1629

Authors: Xue W, Ton H, Zhang J, Xie T, Chen X, Zhou B, Guo Y, Fang J, Wang S, Zhang W

Abstract
Patient‑derived orthotopic glioma xenograft models are important platforms used for pre‑clinical research of glioma. In the present study, the diagnostic ability of magnetic resonance imaging (MRI) was examined with regard to the identification of biomarkers obtained from patient‑derived glioma xenografts and human tumors. Conventional MRI, diffusion weighted imaging and dynamic contrast‑enhanced (DCE)‑MRI were used to analyze seven pairs of high grade gliomas with their corresponding xenografts obtained from non‑obese diabetic‑severe‑combined immunodeficiency nude mice. Tumor samples were collected for transcriptome sequencing and histopathological staining, and differentially expressed genes were screened between the original tumors and the corresponding xenografts. Gene Ontology (GO) analysis was performed to predict the functions of these genes. In 6 cases of xenografts with diffuse growth, the degree of enhancement was significantly lower compared with the original tumors. Histopathological staining indicated that the microvascular area and microvascular diameter of the xenografts were significantly lower compared with the original tumors (P=0.009 and P=0.007, respectively). In one case, there was evidence of nodular tumor growth in the mouse. Both MRI and histopathological staining showed a clear demarcation between the transplanted tumors and the normal brain tissues. The relative apparent diffusion coefficient values of the 7 cases examined were significantly higher compared with the corresponding original tumors (P=0.001) and transfer coefficient values derived from DCE‑MRI of the tumor area was significantly lower compared with the original tumors (P=0.016). GO analysis indicated that the expression levels of extracellular matrix‑associated genes, angiogenesis‑associated genes and immune function‑associated genes in the original tumors were higher compared with the corresponding xenografts. In conclusion, the data demonstrated that the MRI features of patient‑derived xenograft glioma models in mice were different compared with those of the original patient tumors. Differential gene expression may underlie the differences noted in the MRI features between original tumors and corresponding xenografts. The results of the present study highlight the precautions that should be taken when extrapolating data from patient‑derived xenograft studies, and their applicability to humans.

PMID: 32323818 [PubMed – indexed for MEDLINE]

FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis.

February 5, 2021 By Manish Butte

FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis.

J Immunol. 2021 Feb 03;:

Authors: Milanovic M, Shao Z, Estes VM, Wang XS, Menolfi D, Lin X, Lee BJ, Xu J, Cupo OM, Wang D, Zha S

Abstract
Ataxia-telangiectasia mutated (ATM) kinase is a master regulator of the DNA damage response, and loss of ATM leads to primary immunodeficiency and greatly increased risk for lymphoid malignancies. The FATC domain is conserved in phosphatidylinositol-3-kinase-related protein kinases (PIKKs). Truncation mutation in the FATC domain (R3047X) selectively compromised reactive oxygen species-induced ATM activation in cell-free assays. In this article, we show that in mouse models, knock-in ATM-R3057X mutation (Atm⁠ RX ⁠, corresponding to R3047X in human ATM) severely compromises ATM protein stability and causes T cell developmental defects, B cell Ig class-switch recombination defects, and infertility resembling ATM-null. The residual ATM-R3057X protein retains minimal yet functional measurable DNA damage-induced checkpoint activation and significantly delays lymphomagenesis in Atm⁠ RX/RX ⁠ mice compared with Atm⁠ -/- ⁠. Together, these results support a physiological role of the FATC domain in ATM protein stability and show that the presence of minimal residual ATM-R3057X protein can prevent growth retardation and delay tumorigenesis without restoring lymphocyte development and fertility.

PMID: 33536256 [PubMed – as supplied by publisher]

A Structured Approach to Skin and Soft Tissue Infections (SSTIs) in an Ambulatory Setting.

February 5, 2021 By Manish Butte

A Structured Approach to Skin and Soft Tissue Infections (SSTIs) in an Ambulatory Setting.

Clin Pract. 2021 Feb 01;11(1):65-74

Authors: Silverberg B

Abstract
The skin is the largest, and arguably, the most vulnerable organ in the human body. Scratches and scrapes, bites and puncture wounds, impetigo and erysipelas-all these disruptions can lead to pain, swelling, and/or systemic symptoms. In this article, which is based on the Infectious Diseases Society of America’s 2014 guidelines and the World Society of Emergency Surgery and Surgical Infection Society of Europe’s 2018 consensus statement, a structured approach to skin and soft tissue infections (SSTIs) is reviewed, comparing treatment for suppurative and non-suppurative infections, and then discussing specific conditions commonly seen in Primary Care and Urgent Care facilities.

PMID: 33535501 [PubMed]

Measuring only pre-existing Factor VIIa.

February 5, 2021 By Manish Butte

Measuring only pre-existing Factor VIIa.

Int Immunopharmacol. 2020 Jun;83:106424

Authors: Nielsen EW, Østerud B

PMID: 32222638 [PubMed – indexed for MEDLINE]

iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests.

February 5, 2021 By Manish Butte

iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests.

Stem Cell Reports. 2020 02 11;14(2):300-311

Authors: Themeli M, Chhatta A, Boersma H, Prins HJ, Cordes M, de Wilt E, Farahani AS, Vandekerckhove B, van der Burg M, Hoeben RC, Staal FJT, Mikkers HMM

Abstract
RAG2 severe combined immune deficiency (RAG2-SCID) is a lethal disorder caused by the absence of functional T and B cells due to a differentiation block. Here, we generated induced pluripotent stem cells (iPSCs) from a RAG2-SCID patient to study the nature of the T cell developmental blockade. We observed a strongly reduced capacity to differentiate at every investigated stage of T cell development, from early CD7-CD5- to CD4+CD8+. The impaired differentiation was accompanied by an increase in CD7-CD56+CD33+ natural killer (NK) cell-like cells. T cell receptor D rearrangements were completely absent in RAG2SCID cells, whereas the rare T cell receptor B rearrangements were likely the result of illegitimate rearrangements. Repair of RAG2 restored the capacity to induce T cell receptor rearrangements, normalized T cell development, and corrected the NK cell-like phenotype. In conclusion, we succeeded in generating an iPSC-based RAG2-SCID model, which enabled the identification of previously unrecognized disorder-related T cell developmental roadblocks.

PMID: 31956083 [PubMed – indexed for MEDLINE]