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The use of neoadjuvant chemotherapy (NAC) in patients with operable breast cancer allows for assessment of treatment response and subsequent tailoring of adjuvant therapy. Data are limited with respect to outcomes among patients with a heavy residual tumor burden after NAC. We report outcomes in patients who had exceptionally poor responses to NAC: those with9 involved nodes after NAC or with 5 cm or more of residual disease in the breast.Between June 2014 and April 2020, 1511 patients with breast cancer received NAC followed by surgery at our institution. Poor responders, defined as those with positive nodes or residual tumor in the breast, were identified for analysis. Patients were further classified into 3 groups for comparison purposes: (1) 1 to 3 positive nodes; (2) 4 to 9 positive nodes; or (3)9 positive nodes and/or5 cm of residual tumor, which was defined as high-volume residual (HVR). Recurrence and survival outcomes were compared based on residual disease burden after NAC.Among 934 poor responders, 539 patients had 1 to 3 positive nodes (ypN1), 215 had 4 to 9 positive nodes (ypN2), and 180 had HVR disease. Specifically, 118 had9 positive nodes (HVR), and 62 patients had5 cm of residual tumor in the breast. With a median follow-up of 31 months (interquartile range, 18-46), the 5-year overall survival rate was 88% among ypN1, 76% among ypN2, and 72% among patients with HVR disease (P.001). The 5-year distant recurrence-free survival and locoregional recurrence incidences were 82% and 7.6% among ypN1 versus 67% and 8.4% among ypN2 versus 53% and 12% among HVR, respectively.Our work suggests that patients with HVR disease are at high risk for locoregional and distant recurrence as well as death, despite best available standard-of-care treatment. Intensification of locoregional therapies and/or alternative adjuvant systemic treatment may improve outcomes in these poor responders.

To characterize patterns of failure using prostate-specific membrane antigen positron emission tomography (PSMA PET) after radical prostatectomy (RP) and salvage radiotherapy (SRT).Patients with rising PSA post-RP+SRT underwentWe included 133 men who received SRT a median of 20 months post-RP; 56% received SRT to the prostatic fossa alone, while 44% received pelvic SRT. PSMA PET/CT was performed a median of 48 months post-SRT. Overall, 31% of PSMA PET/CT scans were negative, 2% equivocal and 67% had at least 1 positive site. Scan detection was significantly associated with PSA level prior to PSMA PET/CT. Analysis of 89 positive scans demonstrated pelvic nodal (53%) was the most common relapse and fossa relapse was low (9%). Overall, positive scans were pelvic (n = 35, 26%), extra-pelvic nodal (n = 26, 20%) or distant non-nodal failure (n = 28, 21%), and 70% of positive scans were oligorecurrent. We observed similar cumulative incidence for all failure categories and relatively few clinicodemographic associations. Men treated with pelvic SRT had reduced odds of pelvic failure versus exclusive fossa treatment.Pelvic, extra-pelvic nodal, and distant non-nodal failures occur with similar incidence post-SRT. Regional nodal relapse is relatively common, especially with fossa-only SRT. A high oligorecurrence rate suggests a potentially important role for PSMA-guided focal therapies.

Dengue virus (DENV) has developed rapidly in the past few decades and has been becoming the most widespread arbovirus in the world. The vital role of NS2B-NS3 in virus replication and maturation of relevant proteins makes it the most promising target for anti-DENV drug discovery, although none of NS2B-NS3 inhibitors have been approved for the market so far. In this study, potent NS2B-NS3 covalent inhibitors were discovered via chemical modification of a published covalent inhibitor WSL-01 (IC

Nano/microparticles are widely used as vaccine adjuvants to improve antigen stability and enhance immune response. Conformational stability of a given protein was normally assessed using differential scanning calorimetry (DSC) for the optimization of formulation and for ensuring antigen stability in vaccine products. Here, a higher throughput version, namely the microtiter plate-based differential scanning fluorimetry (DSF) method was developed and optimized for assessing the protein thermal stability in the particulate adjuvant-adsorbed form. Using recombinant human papillomavirus (HPV) vaccine antigens, along with several model proteins, enhanced sensitivity and correlation to the well-established differential scanning calorimetry were demonstrated. Higher throughput and much smaller sample consumption (1/10 ∼ 1/20 of the amount needed as compared to DSC) make the plate-based DSF a method of choice for formulation development, particularly during the early developmental phase of a project where the sample amount is usually quite limited.

Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion.

To further improve the performance of chitosan in food processing and preservation, this study investigated the grafting of the caffeic acid onto the chitosan in non-enzymatic and enzymatic systems. Result suggested that the caffeic acid was successfully incorporated into the chitosan in the non-enzymatic system, and the grafting ratio of modified chitosan (CA@CTS-N) was 7.49%. Moreover, lipase had a significant positive effect on the grafting reaction of the chitosan, and the modified chitosan prepared in enzymatic system (CA@CTS-E) obtained a higher grafting ratio, which was 11.82%. In both systems, the carboxyl of the caffeic acid was bonded to the amino of the chitosan and formed carbonyl ammonia. After the introduction of foreign group, many changes occurred in the functional properties of the modified chitosan. First, the water solubility of the chitosan was significantly improved from 0.00285 (native chitosan, CTS) to 0.221 (CA@CTS-N) and 0.774 g/100 mL (CA@CTS-E). The caffeoyl had a significant impact on the emulsifying properties of the chitosan. Compared with those of CTS, the modified chitosan had stronger antioxidation and antibacterial activities against Escherichia coli, Staphylococcus aureus, and Candida albicans. Finally, the pork treated with the modified chitosan exhibited longer shelf life than that treated with CTS.

Graphical abstract, Highlights • Cr(VI) can induce inflammatory, oxidative stress, and apoptosis in rat liver. • Cr(VI) induces inflammatory response in the liver by inhibiting deacetylation. • Oxidative stress caused by Cr(VI) is related to the inhibition of deacetylation. • Cr(VI) aggravates hepatocyte apoptosis by inhibiting deacetylation in rats. • Cr(VI) induces liver injury via inhibition of the deacetylation of Sirt1., Introduction Hexavalent chromium (Cr(VI)), one of the toxic heavy metals, poses a serious threat to human and animal health. Protein acetylation regulates the structure and function of most proteins in a variety of ways. However, the hepatotoxicity of Cr(VI) and whether it is related to deacetylation remains largely unknown. Objectives We aimed to explore the link between the deacetylation of silent information regulator two ortholog 1 (Sirt1) and hepatotoxicity induced by Cr(VI) exposure, and to better clarify the biological mechanism of liver injury induced by Cr(VI). Methods We established a model of liver injury of K2Cr2O7 by injecting rats intraperitoneally for 35 days continuously and adding resveratrol (Res) to further explore the link between deacetylation and hepatotoxicity. Results The results revealed that Cr(VI) induced inflammatory response and apoptosis in hepatocytes. Furthermore, Cr(VI) reduced Sirt1 expression and inhibited the deacetylation of Sirt1 to downstream key transcription factors, including nuclear factor erythroid 2-related factor 2 (Nrf2), Forkhead box O3 (FOXO3), and nuclear factor-kappa B (NF-κB). Conversely, when Res was administered as an activator of Sirt1, the deacetylation of Sirt1 was enhanced, and inflammatory response and apoptosis were significantly alleviated. Conclusion In summary, this work firstly demonstrates that Cr(VI) induces liver injury in rat by inhibiting the deacetylation of Sirt1, which is of positive significance for protecting the natural environment and animal health from chronic Cr poisoning.

In this paper, a method for the enzymatic modification of pectin, in which gallic acid (GA) and propyl gallate (PG) were grafted onto pectin molecules in an aqueous/organic two-phase system catalyzed by lipase, was proposed. The potential reaction mechanism was explored through UV–Vis, FTIR and 1H NMR spectroscopic methods and density functional theory. Results suggested that the lipase played a dual role during the modification by catalyzing the hydrolysis of methyl ester bonds of pectin in the aqueous phase and the esterification between the 4-OH of GA and PG and the –COOH of pectin in the organic phase. Moreover, the effects of GA and PG on the antioxidant and the antibacterial activities of pectin were evaluated, and results showed that the antioxidant and the antibacterial activities of modified pectin were better than those of native pectin. The effect of modified pectin on the quality of fresh bass (Lateolabrax maculatus) was further studied. Results suggested that, compared to control group, the total viable count, histamine level, malondialdehyde content and acid value of bass fillets treated with modified pectin were significantly reduced, whereas the sensory score was significantly increased.

Keratinocyte carcinomas are amenable to many treatments, including radiotherapy (RT). Electronic skin surface brachytherapy (ESSB) enables the precise delivery of radiation without radioisotopes.In this prospective multicenter clinical trial, we characterized early outcomes of ESSB prospectively through both patient- and clinician-reported measures. To corroborate the cosmesis observations, we also assessed patient-reported quality of life (QoL) and adverse events.Patients ≥60 years old with stage TCosmesis and QoL were collected at 97% (99/102) of possible follow-up patient-time points. By 12 weeks post-treatment, 93.9% (31/33) of patient-reported and 96.9% (31/32) of clinician-reported cosmesis outcomes were "good." Compared to baseline, total Skindex-16 score significantly deteriorated at 2 weeks post-treatment (10.5 vs 24.5, p0.001), but significantly improved at 6 weeks (10.5 vs 4.7, p=.014) and 12 weeks (10.5 vs 2.1, p=.001) post-treatment. Total SCI score significantly improved from baseline to 6 weeks (78.4 vs 89.0, p=.001) post-treatment. The most frequent adverse events were radiation dermatitis, skin pain, and pruritus. All adverse events resolved to Grade ≤1 by 12 weeks post-treatment.This prospective, multicenter study demonstrated that ESSB is associated with a high rate of "good" early patient-reported cosmesis and increasing QoL and satisfaction with time. Validated assessments demonstrated a significant improvement in quality of life and resolution of moderate early adverse events by 6-12 weeks after treatment and corroborate the observation of favorable cosmesis.

Pangolins are among the most critically endangered animals due to widespread poaching and worldwide trafficking. Captive breeding is considered to be one way to protect them and increase the sizes of their populations. However, comparative studies of captive and wild pangolins in the context of gut microbiota are rare. Here, the gut microbiome of captive and confiscated-rescued wild pangolins is compared, and the effects of different periods of captivity and captivity with and without antibiotic treatment are considered. We show that different diets and periods of captivity, as well as the application of antibiotic therapy, can alter gut community composition and abundance in pangolins. Compared to wild pangolins, captive pangolins have an increased capacity for chitin and cellulose/hemicellulose degradation, fatty acid metabolism, and short-chain fatty acid synthesis, but a reduced ability to metabolize exogenous substances. In addition to increasing the ability of the gut microbiota to metabolize nutrients in captivity, captive breeding imposes some risks for survival by resulting in a greater abundance of antibiotic resistance genes and virulence factors in captive pangolins than in wild pangolins. Our study is important for the development of guidelines for pangolin conservation, including health assessment, disease prevention, and rehabilitation of wild pangolin populations.

Sodium-ion batteries (SIBs) have drawn much attention due to the abundance and low cost of sodium. However, electrode materials of SIBs displayed sluggish Na+ diffusivity and fatal volume expansion, owing to the larger ionic radius of Na+ ions than Li+ ions. In this work, we built the CoSe2 nanoparticles embedded in graphene nanoscrolls (GNS) as advanced anodes for high-rate SIBs. The CoSe2/C@GNS anodes exhibited a high reversible capacity of 545 mA h g−1 at 0.2 A g−1. Moreover, they showed an outstanding cycling stability of 455 mA h g−1 after 5000 cycles at 1 A g−1, with a capacity retention of 92% calculated from 10th cycle. The CoSe2/C@GNS anode also demonstrate ultrahigh rate capabilities (212.5 mAh g−1 at 50 A g−1). In addition, with a high mass loading (6 mg cm−2), the electrode still displayed a stable capacity (412 mA h g−1 1 A g−1). The fast electron transfer and Na+ ion diffusion kinetics creates the excellent electrochemical properties, on account of the uniform arrangement of nanoparticles and unique reticular crosslinking structure of CoSe2/C@GNS. This strategy could also be constructed other electrode materials, which provides more probabilities for the development of SIBs.

PURPOSE: To investigate predictors associated with post-treatment biopsy outcomes after stereotactic body radiotherapy (SBRT) for localized prostate cancer. MATERIALS AND METHODS: 257 patients treated with prostate SBRT to dose levels of 32.5 Gy to ≥40 Gy in 5–6 fractions underwent a post-treatment biopsy performed approximately two years after treatment to evaluate local control status. 73 had% intermediate-risk disease (n=187) and the remaining 17% (n=43) and 10% (n=27) had low-risk and high-risk disease, respectively. RESULTS: The incidence of positive, negative, and treatment-effect post-treatment biopsies were 15.6%, 57.6%, and 26.8%, respectively. The incidence of a positive biopsy according to dose was 37.5% (n=9/24), 21.4% (n=6/28), 19.4% (n=6/31), and 10.9% (n=19/174) for 32.5 Gy, 35 Gy, 37.5 Gy, and ≥40 Gy, respectively. In a multivariable model, patients treated with SBRT doses of