In this study, a system for oral delivery of oxaliplatin (OXA) was prepared for metronomic chemotherapy to enhance antitumor efficacy and modulate tumor immunity. OXA was complexed with ...Nα-deoxycholyl-l-lysyl-methylester (DCK) (OXA/DCK) and formulated as a nanoemulsion (OXA/DCK-NE). OXA/DCK-NE showed 3.35-fold increased permeability across a Caco-2 cell monolayer, resulting in 1.73-fold higher oral bioavailability than free OXA. In addition, treatment of the B16F10.OVA cell line with OXA/DCK-NE resulted in successful upregulation of immunogenic cell death (ICD) markers both in vitro and in vivo. In a B16F10.OVA tumor-bearing mouse model, treatment with OXA/DCK-NE substantially impeded tumor growth by 63.9 ± 13.3% compared to the control group, which was also greater than the intravenous (IV) OXA group. Moreover, treatment with a combination of oral OXA/DCK-NE and anti-programmed cell death protein-1 (αPD-1) antibody resulted in 78.3 ± 9.67% greater inhibition compared to controls. More important, OXA/DCK-NE alone had immunomodulatory effects, such as enhancement of tumor antigen uptake, activation of dendritic cells in tumor-draining lymph nodes, and augmentation of both the population and function of immune effector cells in tumor tissue as well as in the spleen; no such effects were seen in the OXA IV group. These observations provide a rationale for combining oral metronomic OXA with immunotherapy to elicit synergistic antitumor effects.
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•OXA/DCK-NE was permeated through intestine via bile acid transport-mediated uptake.•The oral bioavailability of OXA/DCK-NE was greater than that of free oxaliplatin.•Oral metronomic OXA/DCK-NE treatment effectively modulated tumor immunity.•OXA/DCK-NE induced immunogenic cell death and enhanced immune cell numbers.•OXA/DCK-NE and αPD-1 exhibited synergistic antitumor effects.
For free-flap monitoring, physical examination still serves as the criterion standard. Blood glucose measurement (BGM) has been suggested to be useful in identifying flap perfusion status. ...Nonetheless, its routine use may not be cost-effective in real-world settings. This study aimed to share the experiences of using BGM for flap monitoring and suggest its potential indications.
Of cases of free flap reconstruction conducted between March 2017 and May 2021, those using BGM for flap monitoring were reviewed. Blood glucose measurement was selectively conducted for the following specific situations, which included encountering a flap showing a reddish discoloration and/or rapid capillary refilling time in the immediate postoperative period, monitoring discolored flaps after conducting a salvage operation, and conducting bloodletting therapy for salvaging congestive flaps. The clinical course and outcomes were evaluated.
Of a total of 203 cases, 35 used BGM for flap monitoring in addition to clinical examination. In 29 cases, BGM was performed to distinguish early hyperemia from true venous insufficiency. All flaps showed BGM greater than 60 mg/dL with a mean value of 115.42, suggesting early hyperemia, and had uneventful postoperative courses. In 3 cases with already discolored flaps after a salvage operation, BGM was conducted 4 times serially every 3 hours and showed a mean value of 81.6 mg/dL with increasing trends. The flaps recovered completely. In the other 3 cases requiring bloodletting therapy, BGM was conducted an average of 11 times at a median interval of 7 hours. The bloodletting therapy was terminated with reference to the value of BGM when it showed greater than 60 mg/dL while the therapy was on hold. All flaps were successfully salvaged except one showing partial necrosis.
Blood glucose measurement may be helpful in assessing flap perfusion and decision making in certain clinical situations and may be useful as an ancillary tool for flap monitoring. Selective application of BGM may contribute to achieving optimal outcomes.
This study was conducted to determine the dietary riboflavin requirement and its effects on growth performance, feed utilization, innate immunity, and diet digestibility of Litopenaeus vannamei. A ...riboflavin-free basal diet (R0) was formulated as a control, and six other diets were prepared by adding riboflavin of 10, 20, 30, 40, 50, and 60 mg/kg to the basal diet (designated as R10, R20, R30, R40, R50, and R60, respectively). Quadruplicate groups of shrimp (initial average weight 0.17±0.00 g) were fed the diets six times a day for 8 weeks. Weight gain, specific growth rate, and protein efficiency ratio were significantly increased by riboflavin (p<0.05). The maximum values were observed in shrimp fed R40 diet. The highest activities of phenoloxidase, nitro blue tetrazolium, superoxide dismutase, and glutathione peroxidase were observed in shrimp fed R40 diet. Lysozyme activity was significantly higher in shrimp fed R30 and R40 diets than that of shrimp fed R60 diet (p<0.05). Intestinal villi were significantly longer in shrimp fed R50 and R60 diets compared to those of all other groups while the shortest villi were observed in R0 group (p<0.05). Intestinal villi were clearly distinguished in shrimp fed higher levels of riboflavin compared to those of shrimp fed R0 and R10 diets. Apparent digestibility coefficients of dry matter and protein in diets were not significantly affected by riboflavin levels (p<0.05). Whole-body proximate composition and hemolymph biochemical parameters were not significantly altered by dietary riboflavin (p<0.05). Therefore, the results of this study indicate that riboflavin is essential to enhance growth performance, feed utilization, nonspecific immunity, and intestine morphology of shrimp. An optimal riboflavin requirement for the maximum growth of L. vannamei seems to be approximately 40.9 mg/kg diet.
Although several studies have found obesity to increase the risk of postoperative morbidity in autologous breast reconstruction, there remains some controversy over the influence of obesity for ...muscle-conserving abdominal flaps, including muscle-sparing transverse rectus abdominis myocutaneous (msTRAM), deep inferior epigastric perforator (DIEP), and superficial inferior epigastric artery (SIEA) flaps. This review evaluates the effects of obesity on complications in breast reconstruction using muscle-conserving abdominal flaps and compares them to those for conventional free transverse rectus abdominis myocutaneous (TRAM) flaps.
A literature search was conducted using MEDLINE, Ovid, and Cochrane databases for studies reporting complication rates for obese and nonobese patients undergoing breast reconstruction using msTRAM, DIEP, and SIEA flaps and conventional free TRAM flaps. The pooled relative risks (RRs) of the obesity for flap-related and donor complications were estimated in the muscle-conserving flaps by meta-analytic methodology and the pooled complication rates in obese patients were compared between muscle-conserving flaps and conventional TRAM flaps. Here, only those studies following the World Health Organization definition of obesity (body mass index ≥ 30 kg/m) were included.
A total of 17 articles were analyzed. Eight studies were used to compute the obesity-related risks of flap-related and donor complications for msTRAM, DIEP, and SIEA flaps. Obesity increased the risk of total flap loss RR, 1.68; 95% confidence interval (CI), 0.85-3.33, partial flap loss (RR, 2.26; 95% CI, 1.01-5.02), abdominal bulge or hernia (RR, 1.72; 95% CI, 1.00-2.95), and overall abdominal complications (RR, 1.53; 95% CI, 1.10-2.14). The results of a pooled analysis with 15 studies are consistent with those of the meta-analysis. In comparison to free TRAM flaps, muscle-conserving abdominal flaps showed a lower pooled incidence of flap loss, fat necrosis, and abdominal bulge or hernia in obese patients.
This review suggests that obesity increases the risk of both flap-related and donor-site complications in breast reconstruction using msTRAM, DIEP, and SIEA flaps. In comparison to conventional TRAM flaps, however, muscle-conserving abdominal flaps may have an advantage in reducing the morbidity in obese patients.
The Google Smartphone Decimeter Challenge (GSDC) was a competition held in 2021, where data from a variety of instruments useful for determining a phone's position (signals from GPS satellites, ...accelerometer readings, gyroscope readings, etc.) using Android smartphones were provided to be processed/assessed in regard to the most accurate determination of the longitude and latitude of user positions. One of the tools that can be utilized to process the GNSS measurements is RTKLIB. RTKLIB is an open-source GNSS processing software tool that can be used with the GNSS measurements, including code, carrier, and doppler measurements, to provide real-time kinematic (RTK), precise point positioning (PPP), and post-processed kinematic (PPK) solutions. In the GSDC, we focused on the PPK capabilities of RTKLIB, as the challenge only required post-processing of past data. Although PPK positioning is expected to provide sub-meter level accuracies, the lower quality of the Android measurements compared to geodetic receivers makes this performance difficult to achieve consistently. Another latent issue is that the original RTKLIB created by Tomoji Takasu is aimed at commercial GNSS receivers rather than smartphones. Therefore, the performance of the original RTKLIB for the GSDC is limited. Consequently, adjustments to both the code-base and the default settings are suggested. When implemented, these changes allowed RTKLIB processing to score 5th place, based on the performance submissions of the prior GSDC competition. Detailed information on what was changed, and the steps to replicate the final results, are presented in the paper. Moreover, the updated code-base, with all the implemented changes, is provided in the public repository. This paper outlines a procedure to optimize the use of RTKLIB for Android smartphone measurements, highlighting the changes needed given the low-quality measurements from the mobile phone platform (relative to the survey grade GNSS receiver), which can be used as a basis point for further optimization for future GSDC competitions.
Recent studies of chloroplast‐localized Sec14‐like protein (CPSFL1, also known as phosphatidylinositol transfer protein 7, PITP7) showed that CPSFL1 is necessary for photoautotropic growth and ...chloroplast vesicle formation in Arabidopsis (Arabidopsis thaliana). Here, we investigated the functional roles of CPSFL1/PITP7 using two A. thaliana mutants carrying a putative null allele (pitp7‐1) and a weak allele (pitp7‐2), respectively. PITP7 transcripts were undetectable in pitp7‐1 and less abundant in pitp7‐2 than in the wild‐type (WT). The severity of mutant phenotypes, such as plant developmental abnormalities, levels of plastoquinone‐9 (PQ‐9) and chlorophylls, photosynthetic protein complexes, and photosynthetic performance, were well related to PITP7 transcript levels. The pitp7‐1 mutation was seedling lethal and was associated with significantly lower levels of PQ‐9 and major photosynthetic proteins. pitp7‐2 plants showed greater susceptibility to high‐intensity light stress than the WT, attributable to defects in nonphotochemical quenching and photosynthetic electron transport. PITP7 is specifically bound to phosphatidylinositol phosphates (PIPs) in lipid‐binding assays in vitro, and the point mutations R82, H125, E162, or K233 reduced the binding affinity of PITP7 to PIPs. Further, constitutive expression of PITP7H125Q or PITP7E162K in pitp7‐1 homozygous plants restored autotrophic growth in soil but without fully complementing the mutant phenotypes. Consistent with a previous study, our results demonstrate that PITP7 is essential for plant development, particularly the accumulation of PQ‐9 and photosynthetic complexes. We propose a possible role for PITP7 in membrane trafficking of hydrophobic ligands such as PQ‐9 and carotenoids through chloroplast vesicle formation or direct binding involving PIPs.
In previous studies, Mott cells, an unusual form of plasma cells containing Ig‐inclusion bodies, were frequently observed in peripheral lymphoid tissues in our IgM Fc receptor (FcμR)‐deficient (KO) ...mouse strain. Because of discrepancies in the reported phenotypes of different Fcmr KO mouse strains, we here examined two additional available mutant strains and confirmed that such enhanced Mott‐cell formation was a general phenomenon associated with FcμR deficiency. Splenic B cells from Fcmr KO mice clearly generated more Mott cells than those from WT mice when stimulated in vitro with LPS alone or a B‐1, but not B‐2, activation cocktail. Nucleotide sequence analysis of the Ig variable regions of a single IgMλ+ Mott‐hybridoma clone developed from splenic B‐1 B cells of Fcmr KO mice revealed the near (VH) or complete (Vλ) identity with the corresponding germline gene segments and the addition of six or five nucleotides at the VH/DH and DH/JH junctions, respectively. Transduction of an FcμR cDNA into the Mott hybridoma significantly reduced cells containing IgM‐inclusion bodies with a concomitant increase in IgM secretion, leading to secreted IgM binding to FcμR expressed on Mott transductants. These findings suggest a regulatory role of FcμR in the formation of Mott cells and IgM‐inclusion bodies.
Enhanced Mott‐cell formation in lymphoid tissues is associated with FcμR deficiency.
B‐1, but not B‐2, B cells generate Mott cells ex vivo upon optimal stimulation.
Mott phenotype of an FcμR‐deficient Mott hybridoma is reversed by the introduction of the FcμR.
The diagnostic value of vertebral artery foraminal segment (V2) ultrasonography remains unclear. This study aimed to estimate the predictive value of V2 Doppler imaging for the detection of ...vertebrobasilar stenosis or occlusion.
Three hundred sixty-four vertebral arteries from 182 patients were investigated. Abnormal Doppler spectra were categorized as high-resistance flow (resistive index ≥0.9), low-resistance flow (resistive index ≤0.5), increased flow velocity (peak systolic velocity ≥137.5 cm/second), or no flow signal. On MR angiography, stenosis and occlusion were defined as >50% narrowing and absent flow signals, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated.
Sixty of 364 vertebral arteries (16.5%) had V2 Doppler abnormalities, while 89 vertebrobasilar arteries (24.5%) had a stenosis or occlusion. The Doppler abnormalities predicted any stenosis or occlusion in the vertebrobasilar artery with a sensitivity of 56.2% and specificity of 96.4% (PPV, 83.3%; NPV, 87.2%). The hypoplastic vertebral artery (lumen diameter ≤2.7 mm) was more frequently associated with vertebrobasilar stenosis or occlusion, and with abnormal Doppler spectra (mostly high-resistance flow), even when it was nonstenotic, than the normal-diameter vertebral artery (p < .001, chi-square test).
The low sensitivity seems to be due to the high prevalence of non-V2 lesions not detected on V2 Doppler imaging, suggesting the necessity for a more extensive sonographic examination beyond V2. However, PPV and NPV ≥80% may suggest its usefulness in clinical practice.
The precise roles of the B‐box zinc finger family of transcription factors in plant stress are poorly understood. Functional analysis was performed on AtCOL4, an Arabidopsis thaliana L. CONSTANS‐like ...4 protein that is a putative novel transcription factor, and which contains a predicted transcriptional activation domain. Analyses of an AtCOL4 promoter‐β‐glucuronidase (GUS) construct revealed substantial GUS activity in whole seedlings. The expression of AtCOL4 was strongly induced by abscisic acid (ABA), salt, and osmotic stress. Mutation in atcol4 resulted in increased sensitivity to ABA and salt stress during seed germination and the cotyledon greening process. In contrast, AtCOL4‐overexpressing plants were less sensitive to ABA and salt stress compared to the wild type. Interestingly, in the presence of ABA or salt stress, the transcript levels of other ABA biosynthesis and stress‐related genes were enhanced induction in AtCOL4‐overexpressing and WT plants, rather than in the atcol4 mutant. Thus, AtCOL4 is involved in ABA and salt stress response through the ABA‐dependent signaling pathway. Taken together, these findings provide compelling evidence that AtCOL4 is an important regulator for plant tolerance to abiotic stress.
