Triple combination of BET plus PI3K and NF-κB inhibitors exhibit synergistic activity in adult T cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell lymphoproliferative malignancy, caused by human T-cell leukemia virus type 1 (HTLV-1). ATL is an orphan disease with no curative drug treatment regimens, urgently needing new combination therapy. HTLV-1-infected cells rely on viral proteins, Tax and HBZ (HTLV-1-b-ZIP factor), to activate the transcription of various host genes that are critical for promoting leukemic transformation. Inhibition of bromodomain and extra-terminal motif (BET) protein was previously shown to collapse the transcriptional network directed by BATF3 super-enhancer and thereby induced ATL cell apoptosis. In the current work, by using xenograft, ex vivo, and in vitro models, we demonstrated that I-BET762 (BETi) synergized with copanlisib (PI3Ki) and bardoxolone methyl (NF-κBi) to dramatically decrease the growth of ATL cells. Mechanistically, the triple combination exhibited synergistic activity by down-regulating the expression of c-MYC while up-regulating the level of the glucocorticoid-induced leucine zipper (GILZ). The triple combination also enhanced apoptosis induction by elevating the expression of active caspase-3 and cleaved PARP. Importantly, the triple combination prolonged the survival of ATL-bearing xenograft mice and inhibited the proliferation of ATL cells from PBMCs of both acute and smoldering/chronic ATL patients. Therefore, our data provide the rationale for a clinical trial exploring the multi-agent combination of BET, PI3K/AKT, and NF-κB inhibitors for ATL patients, and expands the potential treatments for this recalcitrant malignancy.

Six new species of Tonsilla Wang & Yin, 1992 (Araneae: Agelenidae) from southern China, with the first description of the male of T. yanlingensis (Zhang, Yin & Kim, 2000)

Six new species of the spider genus Tonsilla Wang & Yin, 1992 are described from southern China: T. jinyunensis sp. nov. (♂♀) from Chongqing, T. jiugongensis sp. nov. (♂♀) from Hubei, T. subtruculenta sp. nov. (♂♀), T. rutunda sp. nov. (♂♀) and T. yueliangensis sp. nov. (♂) from Guizhou and T. subrostrum sp. nov. (♂♀) from Hunan. In addition, T. yanlingensis (Zhang, Yin & Kim, 2000) is redescribed and its male is described here for the first time. Tonsilla subyanlingensis Liu & Xu, 2020 is transferred to Draconarius Ovtchinnikov, 1999, hence the new combination Draconarius subyanlingensis (Liu & Xu, 2020) comb. nov. is established. The female of T. subyanlingensis Liu & Xu, 2020 should be treated as T. yanlingensis (Zhang, Yin & Kim, 2000). Detailed descriptions, photographs of copulatory organs and somatic features, a distribution map and comparisons with closely related species are presented.

A new species and a new combination for the subfamily Cunaxinae (Acari: Cunaxidae)

A new species of Cunaxidae, namely Cunaxa bagualensis Wurlitzer & Ferla sp. nov., is described and illustrated based on females and males collected in soil and leaf litter in the Atlantic rainforest biome in a rural forest fragment in Mormaço county, Rio Grande do Sul state, Brazil. Additionally, Armascirus livingstoni Laniecka & Kazmierski, 2021 is transferred to Dactyloscirus based on some observations.

Strong SARS-CoV-2 N-specific CD8+ T immunity induced by engineered extracellular vesicles associates with protection from lethal infection in mice.

SARS-CoV-2-specific CD8+ T cell immunity is expected to counteract viral variants in both efficient and durable ways. We recently described a way to induce a potent SARS-CoV-2 CD8+ T immune response through the generation of engineered extracellular vesicles (EVs) emerging from muscle cells. This method relies on intramuscular injection of DNA vectors expressing different SARS-CoV-2 antigens fused at their N-terminus with Nefmut protein, i.e., a very efficient EV-anchoring protein. However, quality, tissue distribution, and efficacy of these SARS-CoV-2-specific CD8+ T cells remained uninvestigated. To fill the gaps, antigen-specific CD8+ T lymphocytes induced by the immunization through the Nefmut-based method were characterized in terms of their polyfunctionality and localization at lung airways, i.e., the primary targets of SARS-CoV-2 infection. We found that injection of vectors expressing Nefmut/S1 and Nefmut/N generated polyfunctional CD8+ T lymphocytes in both spleens and bronchoalveolar lavage fluids (BALFs). When immunized mice were infected with 4.4 lethal doses 50% of SARS-CoV-2, all S1-immunized mice succumbed, whereas those developing the highest percentages of N-specific CD8+ T lymphocytes resisted the lethal challenge. We also provide evidence that the N-specific immunization coupled with the development of antigen-specific CD8+ T-resident memory cells in lungs, supporting the idea that the Nefmut-based immunization can confer a long-lasting, lung-specific immune memory. In view of the limitations of current anti-SARS-CoV-2 vaccines in terms of antibody waning and efficiency against variants, our CD8+ T cell-based platform could be considered for a new combination prophylactic strategy.

Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer

Background and Aims: Pancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy. A major contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success, placing an imperative need for the discovery and application of innovative treatments. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising immunomodulator therapy for PDAC. In this work, we hypothesized RFA promotes local and systemic stromal and immunomodulating effects that can be identified for new combination therapeutic strategies. Methods: To test our hypothesis, a syngeneic PDAC mouse model was performed by symmetrically injecting 100k murine KPC cells in bilateral flanks of C57BL/6 female mice. RFA treatment initiated when tumors reached 200-500 mm3 and was performed only in the right flank. The left flank tumor (non-RFA contralateral side) was used as a paired control for further analysis. Results: RFA promoted a significant reduction in tumor growth rate 4 days after treatment in RFA treated and non-RFA side contralateral tumors from treated mice when compared to controls. Histological analysis revealed a significant increase in expression of cleaved Caspase3 in RFA treated tumors. In addition, collagen deposition and CD31+ cells were significantly elevated in RFA side and non-RFA contralateral tumors from RFA treated mice. Proteome profiling showed changes in C5a and IL-23 in RFA responsive tumors, indicating a role of RFA in modulating intratumoral inflammatory responses. Conclusions: These data indicate RFA promotes local and systemic anti-tumor responses in a syngeneic mouse model of PDAC implicating RFA treatment for local tumors as well as metastatic disease. Keywords: tumor associated macrophages; IL-23; tumor vasculature; ablation induced necrosis

Intranasal dexmedetomidine and intranasal ketamine association allows shorter induction time for pediatric sedation compared to intranasal dexmedetomidine and oral midazolam

Background Non-painful diagnostic procedures require an inactive state for a prolonged time, so that sedation is often needed in younger children to perform the procedures. Our standard of care in this setting consists of the association between oral midazolam (0.5 mg/kg) and intranasal dexmedetomidine (4 mcg/kg). One of the limits of this approach is that the onset of action is quite delayed (up to 55 min) and poorly predictable. We chose to compare this association with intranasal-ketamine and intranasal-dexmedetomidine. Methods This is a “pre-post” study. The study population included the first forty children receiving sedation with the “new” combination intranasal ketamine (3 mg/kg) and intranasal dexmedetomidine (4 mcg/kg) compared to a historical cohort including the last forty children receiving sedation with our standard of care combination of intranasal dexmedetomidine (4mcg/kg) and oral midazolam (0,5 mg/kg). Results The association intranasal dexmedetomidine and intranasal ketamine allowed for a significantly shorter sedation induction time than the combination intranasal dexmedetomidine and oral midazolam (13,5 min versus 35 min). Both group’s cumulative data showed a correlation between age and sedation effectiveness, with younger children presenting a higher success rate and shorter induction time (p 0,001). Conclusions: This study suggests that the ketamine and dexmedetomidine intranasal association may have a shorter onset of action when compared to intranasal dexmedetomidine and oral midazolam.

Twice lost, twice found: A new species of Gonolobus (Apocynaceae: Asclepiadoideae) with a reappraisal of the genus in the Yucatan Peninsula Biotic Province

Gonolobus is reassessed in the Yucatan Peninsula Biotic Province (YPBP). The genus consists of seven taxa in the area: six species and two subspecies. These include a taxon that we propose here as a new species and the treatment of G. yucatanensis as a subspecies of G. stenanthus and the new combination G. stenanthus subsp. yucatanensis is proposed. These two taxa are endemic to the YPBP. The other species are G. barbatus (for which we propose a lectotype), G. cteniophorus, G. fraternus, G. glaberrimus, and G. leianthus. The new species is G. caamalii Carnevali & R. Duno, restricted to the Yucatán state in Mexico and distinguished by its corolla lobes with a dark purple (almost black) longitudinal, callose band along the proximal 2/3 on the right side of the lobes and a 1.1–1.3 mm broad, annular, continuous dark purple-black band surrounding the gynostemium and corona at the base of the corolla lobes. It appears related to G. leianthus from southern Megamexico, a species from humid forests at higher elevations and that differs in its larger flowers with broader corolla lobes and a strikingly different color pattern in the flowers. The new species is described, illustrated, and discussed. Entries for all Gonolobus species from the YPBP include a brief discussion and specimen citations. The conservation status of the Gonolobus taxa endemic to the YPBP are assessed either as as Endangered (EN) or as Near threatened (NT). Distributional maps for all Gonolobus from the area covered are presented. Finally, we offer a key to Gonolobus of the YPBP.

Changes in knowledge coupling and innovation performance: the moderation effect of network cohesion

Purpose Collaborative research and development have remained a pertinent mechanism for conducting technological innovations. With the lens of knowledge-based view (KBV), this study aims to examine the role of changes in knowledge couplings and network cohesion to elevate innovation performance. Design/methodology/approach Data analysis has been performed on 53,459 patents through regression analysis with random effects. These independent and joint patents are extracted from Derwent Innovation Database. Findings Findings explicate that change in external existing or existing and new knowledge couplings have inverted U-shaped effects on a firm’s innovation performance. Changes in internal existing or existing and new knowledge couplings have direct positive effects on firm’s innovation performance. The moderation effect of network cohesion flattens the inverted U-shaped effect of external new and existing knowledge coupling, whereas it has no significant effect on external existing knowledge coupling. Network cohesion further elevates the effects of internal knowledge couplings – existing or existing and new. Research limitations/implications This study theoretically contributes to KBV and innovation management literature by highlighting the scope of changes in internal and external knowledge couplings and subsequent output. Network cohesion flattens the curviness of changes in external new and existing knowledge couplings, which is a contribution to strategic management literature. Practical implications Organizations need to carefully manage changes in knowledge couplings and ensure their benefits (obtain new knowledge domain or new combination) outweigh liabilities (damages to organizational routines or increase in collaboration costs). Managers must consider four kinds of knowledge coupling changes along with developing network cohesion as an R&D strategy. Originality/value This study is one of its types to flatten the curve through network cohesion. This study divided the changes in knowledge coupling into four types and two dimensions; external existing and new and existing knowledge couplings and internal existing and new and existing knowledge couplings.

Synergistic In Vitro Antimicrobial Activity of Triton X-100 and Metformin against Enterococcus faecalis in Normal and High-Glucose Conditions

The prevention and treatment of oral diseases is more difficult in diabetic patients with poorly controlled blood glucose levels. This study aims to explore an effective, low-cytotoxicity medication for root canal treatment in diabetic patients. The antibacterial effect of the combination of Triton X-100 (TX-100) and metformin (Met) on Enterococcus faecalis (E. faecalis) was evaluated by determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration required to kill 99% bacteria (MBC99) and by conducting dynamic time-killing assays. While the antibiofilm activity was measured by crystal violet (CV) assay, field emission scanning electron microscope (FE-SEM), confocal laser scanning microscope (CLSM) and colony-forming unit (CFU) counting assays. The expression of relative genes was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR), and the cytotoxicity of the new combination on MC3T3-E1 cell was also tested. Results showed that the antibacterial and antibiofilm activities of Met could be significantly enhanced by very low concentrations of TX-100 in both normal and high-glucose conditions, with a much lower cytotoxicity than 2% chlorhexidine (CHX). Thus, the TX-100 + Met combination may be developed as a promising and effective root canal disinfectant for patients with diabetes.