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Interleukin 12 (IL12) is a potent pro-inflammatory chemokine with multifunction, including promoting cytotoxic T-cell-mediated killing of cancer cells. Honokiol order IL12-based cancer gene therapy can overcome IL12's life-threatening adverse effects, but its clinical translation has been limited by the lack of systemic gene-delivery vectors capable of efficiently transfecting tumors to produce sufficient local IL12. Macrophages inherently excrete IL12, and tumor-associated macrophages (TAMs) are the major tumor component taking up a large fraction of the vectors arriving in the tumor. It is thus hypothesized that a gene vector efficiently transfecting both cancer cells and TAMs would make the tumor to produce sufficient IL12; however, gene transfection of TAMs is challenging due to their inherent strong degradation ability. Herein, an IL12 gene-delivery vector is designed that efficiently transfects both cancer cells and TAMs to make them as a factory for IL12 production, which efficiently activates anticancer immune responses and remodels the tumor microenvironment, for instance, increasing the M1/M2 ratio by more than fourfold. Therefore, the intravenously administered vector retards tumor growth and doubles survival in three animal models' with negligible systemic toxicities. This work reports the first nonviral IL12 gene delivery system that effectively makes use of both macrophages and tumor cells.
Guidelines for follow-up after oral cancer treatment are not site-specific and encompass the entire head and neck area rather than the oral cavity alone. This one-size-fits-all protocol disregards the differences in aetiology, treatment and differential distribution of new disease between the subsites. With the effectiveness of follow-up in early detection of new disease being put into question, the focus of follow-up programmes might shift to other aspects of survivorship care. Personalization of follow-up is important, considering patient-specific features and needs. Furthermore, the COVID-19 pandemic urges us to rethink our follow-up practice.
This paper discusses ways in which routine follow-up in patients treated for oral cancer can be optimized. Patients with a high risk of new disease might benefit from an intensified follow-up regimen, whilst patients with a low risk of new disease, a low chance of cure or limited life expectancy could benefit from a de-intensified follow-up regimen. The latter could include a shorter follow-up period and focus on goals other than early detection of new disease. Education of patients to report new symptoms early is of vital importance as the majority of new disease presents symptomatically. Other health care professionals such as specialist nurses and dentists need to play an important leading role in survivorship care. Remote consultations may be useful to perform more efficient and patient-centred follow-up care.
Routine follow-up needs to be seen as an integrated part of an individualized survivorship plan that is provided by the entire multidisciplinary team.
Routine follow-up needs to be seen as an integrated part of an individualized survivorship plan that is provided by the entire multidisciplinary team.The illegal harvest of marine species within exclusive economic zones can have a strong impact on the function of local ecosystems and livelihoods of coastal communities. The complexity of these problems is often overlooked in the development of solutions, leading to ineffective and sometimes harmful social and environmental outcomes. One-dimensional, oversimplified perspectives can lead to conservation prescriptions that exacerbate social stressors. This is particularly critical in the case of international illegal trade of endangered, high-value species, which generate a value chain in which artisanal fishers are the first operational and often the weakest link of an intricate web. We examined 2 illegal fisheries, totoaba (Totoaba macdonaldi) and sea cucumber (Isostichopus badionotus and Holothuria floridana), in Mexico. Although these are 2 separate and independent fisheries, important ecological (resource condition, fishery impacts at the ecosystem level) and social (governance, markets) similarities improve understanding of their complexity. Our findings are relevant globally and show the need for interdisciplinary decision-making groups, community engagement, and the development of demand reduction measures.The synthesis of 1,3-oxazoles from symmetrical and unsymmetrical alkynes was realized by an iodonium cation-pool electrolysis of I2 in acetonitrile with a well-defined water content. Mechanistic investigations suggest that the alkyne reacts with the acetonitrile-stabilized I+ ions, followed by a Ritter-type reaction of the solvent to a nitrilium ion, which is then attacked by water. The ring closure to the 1,3-oxazoles released molecular iodine, which was visible by the naked eye. Also, some unsymmetrical internal alkynes were tested and a regioselective formation of a single isomer was determined by two-dimensional NMR experiments.The yeast DNA polymerase gamma, Mip1, is a useful tool to investigate the impact of orthologous human disease variants on mitochondrial DNA (mtDNA) replication. However, Mip1 is characterized by a C-terminal extension (CTE) that is not found on orthologous metazoan DNA polymerases, and the CTE is required for robust enzymatic activity. Two MIP1 alleles exist in standard yeast strains, encoding Mip1[S] or Mip1[Σ]. Mip1[S] is associated with reduced mtDNA stability and increased error rates in vivo. Although the Mip1[S] allele was initially identified in S288c, the Mip1[Σ] allele is widely present among available yeast genome sequences, suggesting that it is the wild-type (WT) allele. We developed a novel non-radioactive polymerase gamma assay to assess Mip1 functioning at its intracellular location, the mitochondrial membrane. Membrane fractions were isolated from yeast cells expressing full-length or CTE truncation variants of Mip1[S] or a chimeric Mip1[S] isoform harboring the Mip1[Σ]-specific T661 residue (cMip1 T661). Relative incorporation of digoxigenin (DIG)-11-deoxyuridine monophosphate (DIG-dUMP) by cMip1 T661 was higher than that by Mip1[S]. A cMip1 T661variant lacking 175 C-terminal residues maintained WT levels of DIG-dUMP incorporation, whereas the C-terminal variant lacking 205 residues displayed a significant decrease in incorporation. Newly synthesized DIG-labeled DNA decreased during later phases of reactions carried out at 37°C, suggesting temperature-sensitive destabilization of the polymerase domain and/or increased shuttling of the nascent DNA into the exonuclease domain. Comparative analysis of Mip1 enzyme functions using our novel assay has further demonstrated the importance of the CTE and T661 encoded by MIP1[Σ] in yeast mtDNA replication.
This preliminary longitudinal study examined timing features and type of interaction between infant boys and their mothers with attention deficit hyperactivity disorder (ADHD) symptoms METHOD Ten infants and their mothers with ADHD symptoms and 10 control dyads were video recorded at home during free play interactions when infants were 2-, 4-, 6-, and 9-month old. Microanalysis of the video recordings was carried out to assess synchronization, turn-taking, and type of interaction. Infants' temperament was also assessed RESULTS ADHD dyads showed shorter synchronization at 2 months and shorter duration of Joint Attention. Partial least squares regression analysis revealed that infant's ability for Joint Attention is predicted mainly by duration of maternal behavior as well as by earlier forms of communication, that is, protoconversations.
The data from our preliminary study suggest thatmothers with ADHD symptoms may have difficulties maintaining their behavior for enough time possibly due to the core symptoms of the disorder, that is, inattention, hyperactivity, and impulsivity. This maternal deficit seems to affect temporal coordination with their infants and maybe the development of more complex forms of interaction. Clinical implications of these findings are also discussed.
The data from our preliminary study suggest that mothers with ADHD symptoms may have difficulties maintaining their behavior for enough time possibly due to the core symptoms of the disorder, that is, inattention, hyperactivity, and impulsivity. This maternal deficit seems to affect temporal coordination with their infants and maybe the development of more complex forms of interaction. Clinical implications of these findings are also discussed.Dithioacetals are a frequently used motif in synthetic organic chemistry and have recently seen increasing attention as structural motif in promising antiviral agents against plant pathogens. Most existing reports, however, only discuss symmetrical dithioacetals. Examples of mixed dithioacetals are scarce and no general method for the selective synthesis of these compounds exists. Herein, a synthetically simple general one-step protocol was developed for the synthesis of a broad range of unsymmetrical dithioacetals consisting of one aromatic and one aliphatic thiol moiety from the corresponding aldehyde/thiol mixture. The mixed S,S-acetals were obtained in high yields, and a great variety of functional groups was tolerated. Kinetic control enabled an excellent selectivity in regard to the unsymmetrical dithioacetal.
Biliary perfusion is considered to contribute to biliary diseases, but routine imaging methods are insufficient to show it. This research investigated the ability of contrast-enhanced ultrasound (CEUS) for biliary perfusion in a biliary ischemia model.
This research consisted of 2 parts. First, to determine whether CEUS enhancement of the tiny biliary wall represents biliary perfusion, a vascular tracer was used as a reference to evaluate the consistency with the enhancement of the biliary wall on CEUS and the staining by the vascular tracer under the conditions of occluded and recovered biliary perfusion. In the second part, the ability of CEUS for biliary ischemia was further evaluated with microvascular density measurement as a reference. The enhancement patterns were assigned CEUS scores, in which higher scores meant more decreased enhancement, and the diagnostic ability of CEUS was assessed by a receiver operating characteristic curve analysis.
The biliary wall was unstained by the vascular tracer and nonenhanced on CEUS when biliary perfusion was interrupted and was stained blue and enhanced after recovery. The biliary wall in the ischemia surgery group showed lower microvascular density measurements (P < .001), decreased enhancement levels (P < .001), and higher CEUS scores (P < .001). When a CEUS score of 3 or higher (obvious decrease of the biliary wall to hypoenhancement or nonenhancement in the arterial phase or rapid wash-out to nonenhancement in the portal venous phase) was applied, CEUS had sensitivity of 87.8%, specificity of 98.3%, accuracy of 93.8%, and an area under the receiver operating characteristic curve of 0.98.
Contrast enhancement of the biliary wall on CEUS represents biliary perfusion and has reasonably good diagnostic performance for biliary ischemia in an experimental animal setting.
Contrast enhancement of the biliary wall on CEUS represents biliary perfusion and has reasonably good diagnostic performance for biliary ischemia in an experimental animal setting.
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