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Active ingredients of Chinese medicine (AIFCM) are pharmacological substances taken from traditional Chinese medicine that show promise in treating gastrointestinal cancer. Compared with traditional chemotherapeutic drugs, AIFCM have advantages such as multi-target and multi-level treatment of gastrointestinal cancer. Nanocarriers have the following advantages, better bioavailability, passive or active targeting of tumor sites and responsive release of drugs. The use of nanocarriers for delivery of AIFCM in treatment of gastrointestinal cancer, can overcome the disadvantages of some AIFCM, such as insolubility and low bioavailability. In this review, we first outline the background on gastrointestinal cancer, main curative factors and conventional therapeutic approaches. Then, the mechanisms for AIFCM in gastrointestinal cancer therapy are presented in the following four aspects: gene regulation, immune modulation, cellular pathway transduction, and alteration of intestinal flora. Thirdly, preparation of various nanocarriers and results when combining AIFCM in gastrointestinal cancer are presented. Fourth, application of novel targeted nanocarriers and responsive nanocarriers in gastrointestinal tumors is further introduced. Finally, the application of AIFCM in the treatment of gastrointestinal cancer is summarized and prospected, hoping to shed some light on the nanocarrier-bound AIFCM in the treatment of gastrointestinal cancer.

IntroductionDefault mode network (DMN) is the most involved network in the study of brain development and brain diseases. Resting-state functional connectivity (rsFC) is the most used method to study DMN, but different studies are inconsistent in the selection of seed. To evaluate the effect of different seed selection on rsFC, we conducted an image-based meta-analysis (IBMA).MethodsWe identified 59 coordinates of seed regions of interest (ROIs) within the default mode network (DMN) from 11 studies (retrieved from Web of Science and Pubmed) to calculate the functional connectivity; then, the uncorrected t maps were obtained from the statistical analyses. The IBMA was performed with the t maps.ResultsWe demonstrate that the overlap of meta-analytic maps across different seeds’ ROIs within DMN is relatively low, which cautions us to be cautious with seeds’ selection.DiscussionFuture studies using the seed-based functional connectivity method should take the reproducibility of different seeds into account. The choice of seed may significantly affect the connectivity results.

PurposeThe purpose of this study is to show how gradual strength degradation of metal beams under cyclic bending up to fatigue failure is simulated based on a new elastoplasticity model free of any yield criterion.Design/methodology/approachA new approach is proposed toward accurately and explicitly prescribing evolution of non-uniform stress distribution on beam cross-section under cyclic bending and, as such, gradual degradation of the bending strength can be directly determined.FindingsExplicit results for the bending response in a whole cyclic process up to fatigue failure are obtained and the fatigue characteristic curve is for the first time simulated directly between the curvature amplitude and the cycle number to failure.Originality/valueFirst, explicit and accurate determination of the non-uniform stress distribution on beam cross-section is achieved with asymptotic softening effects. Second, degradation of the bending strength can be directly deduced cycle by cycle. Finally, the relationship between the bending moment and the curvature is calculated using new and efficient numerical algorithms, thus bypassing usual time-consuming calculations with finite element procedures. Numerical results are presented and in good agreement with experimental data.

The association between muscle mass and cognitive impairment (CI) is conflicting. We aimed to evaluate and compare the associations of muscle strength, muscle mass and CI risk in maintenance hemodialysis (MHD) patients.We conducted a multicenter, cross-sectional study. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) score. Muscle strength was assessed by hand grip strength (HGS), muscle mass was assessed by lean tissue mass (LTM). Education status was divided into two groups: lower education status (senior middle school and below) and higher education status (high school and above). Multivariable logistic regression models and subgroup analyses were performed. Receiver-operating characteristic (ROC) analyses were conducted to compare their predictive power in discriminating CI.2827 adult MHD patients were included in our final analysis. Patients in the lowest quartile of HGS was 2.82-fold as likely to have CI as compared to those in the highest quartile, while participants in the lowest quartile of LTM group were 1.52-fold as likely to have CI, when compared with the highest quartile group of LTM after adjusting for age, gender and education level. The association persisted in all subgroups except for women and well-educated participants. There was a significant interaction between HGS and education status on CI and age played an interactive role in the association between LTM and incident CI (P for interaction 0.05). The AUC value of the HGS was significantly higher than that of LTM (0.69 VS 0.63, P 0.001).Muscle strength performed better than muscle mass in identifying individuals at high risk of CI, particularly in male and less educated Chinese MHD patients.Level V, cross-sectional study.

CXC chemokine receptor 4 (CXCR4), a member of the G-protein-coupled receptor family, plays an important role in host immune responses. Within the teleost lineage, there are two paralogs of CXCR4; however, the role of CXCR4 in teleost B cells is poorly understood. In this study, we determined the cDNA sequences of the two CXCR4 paralogs from the Japanese sea bass (Lateolabrax japonica; LjCXCR4a and LjCXCR4b). Sequence and phylogenetic tree analyses revealed that LjCXCR4a and LjCXCR4b are most closely related to CXCR4a and CXCR4b, respectively, in the large yellow croaker (Larimichthys crocea). CXCR4 transcripts were mainly expressed in the gills, and their expression in different tissues was altered upon infection with Vibrio harveyi. LjCXCR4a and LjCXCR4b protein levels were upregulated in infected B cells. Knockdown of LjCXCR4a and LjCXCR4b in B cells by RNA interference, the phagocytic activity of B cells was not affected. Furthermore, knockdown of LjCXCR4a, not of LjCXCR4b, was observed to inhibit LjIgM expression in lipopolysaccharide-stimulated B cells. In addition, knockdown of LjCXCR4a, not of LjCXCR4b, was found to reduce reactive oxygen species levels in B cells. Our results indicate that LjCXCR4a and LjCXCR4b modulate the immune response of Japanese sea bass B cells against bacterial infection, albeit via different pathways.

In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on diabetic cardiomyopathy (DCM), as the spontaneous cardiac dysfunction, cardiac cell hypertrophy, and cardiac fibrosis occurred in DICAR deficiency (DICAR+/−) mice, whereas the DCM was alleviated in DICAR-overexpressed DICARTg mice. At the cellular level, we found that overexpression of DICAR inhibited, but knockdown of DICAR enhanced the diabetic cardiomyocyte pyroptosis. At the molecular level, we identified that DICAR-VCP-Med12 degradation could be the underlying molecular mechanism in DICAR-mediated effects. The synthesized DICAR junction part (DICAR-JP) exhibited a similar effect to the entire DICAR. In addition, the expression of DICAR in circulating blood cells and plasma from diabetic patients was lower than that from health controls, which was consistent with the decreased DICAR expression in diabetic hearts. DICAR and the synthesized DICAR-JP may be drug candidates for DCM.

Chiral molecules show differences in their chemical and optical properties due to different spatial arrangements of the atoms in the two enantiomers. A common way to optically differentiate them is to detect the disparity in the absorption of light by the two enantiomers, i.e. the absorption circular dichroism (CD). However, the CD of typical molecules is very small, limiting the sensitivity of chiroptical analysis based on CD. Cavity ring-down spectroscopy (CRDS) is a well-known ultrasensitive absorption spectroscopic method for low-absorbing gas-phase samples because the multiple reflections of light in the cavity greatly increase the absorption path. By inserting a prism into the cavity, the optical mode undergoes total internal reflection (TIR) at the prism surface and the evanescent wave (EW) enables the absorption detection of condensed-phase samples within a very thin layer near the prism surface, called EW-CRDS. Here, we propose an ultrasensitive chiral absorption spectroscopy platform using a dielectric metasurface-assisted EW-CRDS. We theoretically show that, upon linearly polarized and oblique incidence, the metasurface exhibits minimum scattering and absorption loss, introduces negligible polarization change, and locally converts the linearly polarized light into near fields with finite optical chirality, enabling CD detection with EW-CRDS that only works with linearly polarized light. We evaluate the ring-down time in the presence of chiral molecules and determine the sensitivity of the cavity as a function of total absorption from the molecules. The findings open the avenue for an ultrasensitive thin film detection of the chiral molecules using the CRDS techniques., Comment: 6 pages and 4 figures

Toward accurately simulating both hardening and softening effects for metals up to failure, a new finite strain elastoplastic J2-flow model is proposed with the yield strength therein as a function of the plastic work in the explicit form. With no need to identify any adjustable parameters, the uniaxial stress-strain response predicted from this new model is shown to automatically and accurately match any given data from monotonic uniaxial extension tests of bars. As such, the objectives in three respects are achieved for the first time, i.e., (i) both the hardening and softening effects up to failure can be simulated in the sense of matching test data with no errors, (ii) the usual tedious implicit procedures toward identifying numerous unknown parameters need not be involved and can be totally bypassed, and (iii) the model applicability can be ensured in a broad sense for various metallic materials with markedly different transition effects from hardening to softening. With the new model, the complete response features of stretched bars and twisted tubes up to failure are studied, including the failure effects of bars under monotonic extension and tubes under monotonic torsion and, furthermore, the fatigue failure effects of bars under cyclic loading. The results show accurate agreement with the uniaxial data, and the results for both the shear stress and the normal stress at the finite torsion display realistic hardening-to-softening transition effects for the first time.

Kaempferol (KAE) is a natural flavonoid compound with antitumor activity. However, the low aqueous solubility, poor chemical stability and suboptimal bioavailability greatly restricted its clinical application of cancer. In order to overcome these shortages and enhance the antitumor effect of KAE, we developed a kaempferol nanosuspensions (KAE-NSps) with D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) as stabilizer, screened the optimal preparation process, and investigated the basic properties and the antitumor effect in the study. The results demonstrated that the particle size was 186.6 ± 2.6 nm of the TPGS-KAE-NSps optimized, the shape of which was fusiform under the transmission electron microscope. The 2% (w/v) glucose was used as the cryoprotectant for TPGS-KAE-NSps, whose drug loading content was 70.31 ± 2.11%, and the solubility was improved prominently compared to KAE. The stability and biocompatibility of TPGS-KAE-NSps were favorable, which had a certain sustained release effect. Moreover, TPGS-KAE-NSps clearly seen to be taken in the cytoplasm exhibited a stronger cytotoxicity and suppression of cell migration, higher apoptosis rate and more intracellular ROS production compared to KAE in vitro cell experiments. In addition, TPGS-KAE-NSps showed a stronger inhibition of tumor growth (the tumor inhibition rate of high dose intravenous injection group was 68.9 ± 1.46%) than KAE with no obvious toxicity on 4T1 tumor-bearing mice. Overall, TPGS-KAE-NSps prepared improved the defect and the antitumor effect of KAE notably, which was a promising nanodrug delivery system for KAE and was expected to become a clinical antitumor drug.

Based on both positive psychology and the gene × environment research paradigm, the current study constructed a moderated mediation model to explore the relationship between childhood maltreatment ...

Biological cells in vivo typically reside in a dynamic flowing microenvironment with extensive biomechanical and biochemical cues varying in time and space. These dynamic biomechanical and biochemical signals together act to regulate cellular behaviors and functions. Microfluidic technology is an important experimental platform for mimicking extracellular flowing microenvironment in vitro. However, most existing microfluidic chips for generating dynamic shear stress and biochemical signals require expensive, large peripheral pumps and external control systems, unsuitable for being placed inside cell incubators to conduct cell biology experiments. This study has developed a microfluidic generator of dynamic shear stress and biochemical signals based on autonomously oscillatory flow. Further, based on the lumped-parameter and distributed-parameter models of multiscale fluid dynamics, the oscillatory flow field and the concentration field of biochemical factors has been simulated at the cell culture region within the designed microfluidic chip. Using the constructed experimental system, the feasibility of the designed microfluidic chip has been validated by simulating biochemical factors with red dye. The simulation results demonstrate that dynamic shear stress and biochemical signals with adjustable period and amplitude can be generated at the cell culture chamber within the microfluidic chip. The amplitudes of dynamic shear stress and biochemical signals is proportional to the pressure difference and inversely proportional to the flow resistance, while their periods are correlated positively with the flow capacity and the flow resistance. The experimental results reveal the feasibility of the designed microfluidic chip. Conclusively, the proposed microfluidic generator based on autonomously oscillatory flow can generate dynamic shear stress and biochemical signals without peripheral pumps and external control systems. In addition to reducing the experimental cost, due to the tiny volume, it is beneficial to be integrated into cell incubators for cell biology experiments. Thus, the proposed microfluidic chip provides a novel experimental platform for cell biology investigations.

BackgroundThe clinical outcomes are not always favorable in certain thyroid cancer patients. The effect of Forkhead-box family on immune cells infiltration and tumor microenvironment in thyroid cancer was explored. The role of FOXP2 in tumor invasion and recurrence was investigated consequently.MethodsTIMER and GEPIA were firstly employed to compare FOXPs expression in normal and cancer tissues from multiple human cancers. The results from database were confirmed by quantitative Real Time-PCR and Western blot in matched thyroid cancer and adjacent normal tissues, in addition to a panel of thyroid cancer cell lines and normal thyroid cell. GEPIA platform was employed to discover the possibility of FOXPs as prognostic indicator. TISIBD and UACLCAN were then employed to estimate the influence of FOXPs on lymph node metastasis and tumor staging. GEPIA analysis was initially employed to analyze correlation of FOXPs and tumor immune infiltrating cells, and TIMER dataset was then included for standardization according to tumor purity.ResultDifferent member of FOXPs showed divergence in expression in various cancer tissues. Lower FOXP1, FOXP2 and higher FOXP3, FOXP4 levels could be identified in thyroid cancer tissues when compared with matched normal tissue. There was an inverse correlation between FOXP2, FOXP4 and immune invasion, whereas FOXP1 and FOXP3 were positively correlated. FOXPs showed remarkable correlations with multiply immune cells. More importantly, only FOXP2 showed the significant effect on recurrence and tumor staging.ConclusionAs immune regulatory factor, the reduction of FOXP2 may affect tumor microenvironments and immune cells infiltration, enhance tumor immune escape, and promote recurrence of thyroid cancer. FOXP2 could be a new potential diagnostic and prognostic marker.

Heat stress (HS) affects the development of porcine gametes and embryos negatively, induces the decrease of reproductive ability significantly, threatens global pig production. Ginsenoside Re (GRe), is a main bioactive component of ginseng, shows very specific anti-apoptotic, antioxidant and anti-inflammatory activities. To investigate the alleviating effect of GRe on the in vitro maturation of porcine oocyte under the HS, the polar body extrusion rate, intracellular levels of reactive oxygen species (ROS) and glutathione (GSH), ATP content, mitochondrial membrane potential (MMP) were assessed. For the current study, porcine cumulus-oocyte complexes (COCs) randomly divided into four groups: the control, GRe, HS and HS + GRe group. The results showed that HS inhibited the cumulus cell expansion and polar body extrusion rate, the levels of GSH and MMP, the ATP content, the gene expression of Nrf2 of porcine oocytes and the parthenogenetic activation (PA) embryo development competence, but GRe treatment could partly neutralize these adverse effects. Furthermore, HS increased the ROS formation and percentage of apoptosis, the gene expression of HSP90, CASP3 and CytoC of porcine oocytes, but GRe could weaken the effect on Cyto C and BAX expression induced by HS. Taken together, these results showed that the presence of GRe during in vitro maturation protects porcine oocytes from HS. These findings lay a foundation for GRe may be used as a potential protective drug to protect porcine oocytes against HS damage.

Methylprednisolone pulse treatment is currently used for optic neuritis. It can speed visual recovery, but does not improve the ultimate visual outcomes. Recent studies have reported that miR-125a-5p has immunomodulatory effects on autoimmune diseases. However, it remains unclear whether miR-125a-5p has effects on optic neuritis. In this study, we used adeno-associated virus to overexpress or silence miR-125a-5p in mice. We found that silencing miR-125a-5p increased the latency of visual evoked potential and aggravated inflammation of the optic nerve. Overexpression of miR-125a-5p suppressed inflammation of the optic nerve, protected retinal ganglion cells, and increased the percentage of Treg cells. Our findings show that miR-125a-5p exhibits anti-inflammatory effects through promoting the differentiation of Treg cells.

Lateral neck dissection (LND) is a necessary treatment for thyroid cancer with lateral lymph node metastasis. However, the defect created during open surgery leaves a visible scar on the neck. With advancements in surgical technology, many robotic and endoscopic surgical techniques have been reported as alternatives to open surgery. In this study, we present a case series demonstrating the successful application of a novel hybrid approach for endoscopic LND and a review of different surgical approaches for “scarless” (at the neck) LND. We performed endoscopic LND via a combined chest and transoral approach in 24 patients between January 2021 and March 2022. The surgery was completed successfully in all patients with an average operation time of 298.1 ± 72.9 min. The numbers of positive/retrieved lymph nodes at levels II, III-IV, and VI were 0.7 ± 0.9/8.4 ± 4.1, 3.6 ± 2.7/19.5 ± 6.8, and 4.9 ± 3.9/10.3 ± 4.5, respectively. Complications included transient hypoparathyroidism in 10 patients, transient recurrent laryngeal nerve injury in 1 patient, internal jugular vein (IJN) injury in 1 patient, IJN sacrifice due to cancer invasion in 1 patient, and chyle leak in 1 patient, and no cases of tumor recurrence were observed during follow-up. The present case series indicates that the combined chest and transoral approach is feasible and effective for performing LND. Our review of different approaches for “scarless” (at the neck) LND identified advantages and disadvantages for all techniques. Our novel approach has unique advantages, and thus, it can provide an ideal surgical procedure for specific papillary thyroid carcinoma patients.

Using the differential susceptibility model, the present study examined how (mediator = Internet addiction) and when (moderator = 5-HTR1A gene rs6449693) did negative life events influence college students’ depression. A total of 301 Chinese college students (mean age = 19.15 years, SD = 0.93) from southern China completed anonymous questionnaires (the Center for Epidemiological Studies Depression Scale, the Adolescent Self-Rating Life Events Check List, and the Chinese Version of the Internet Addiction Scale). Our findings revealed that negative life events, Internet addiction, and college students’ depression were significantly and positively associated with each other. Internet addiction mediated the relationship between negative life events and college students’ depression. Further, 5-HTR1A gene rs6449693 polymorphism moderated the relationship between negative life events and college students’ depression; specifically, allele G is the susceptibility reason which is manifested, as depression scores of individuals with high level of allele G are significantly lower than those with low level allele A. These findings underscore the importance of the differential susceptibility model in understanding how and when negative life events impact college students’ depression.

Objectives To investigate whether anemia of inflammation (AI) occurs in periodontitis patients and to further explore underlying pathogenesis of periodontitis-related AI by an experimental periodontitis model. Background Previous studies have reported periodontitis patients could show a tendency toward AI. However, the relationship between periodontitis and AI remains unclear, and the related pathological mechanisms have not been identified. Materials and methods Periodontal clinical parameters, inflammatory markers, and anemia-related indicators were compared between 98 aggressive periodontitis (AgP) patients and 103 healthy subjects. An experimental periodontitis model was induced by ligature placement in mice. The changes in mice inflammatory markers, anemia indicators, hepcidin mRNA expression, and serum hepcidin concentrations were measured. Human and mouse liver cells were treated with interleukin-6 (IL-6) for analyzing the changes in hepcidin expression based on mRNA and protein levels. Results AgP patients exhibited higher white blood cell counts, IL-6, and C-reactive protein. Adjusted linear regression analyses showed correlations between AgP and decreased hemoglobin (HGB) and hematocrit (HCT). The ligature-induced periodontitis caused systemic inflammation and elevated IL-6 levels. Lower red blood cell counts, HGB, and HCT were detected, whereas the levels of hepcidin mRNA expression and serum hepcidin concentrations increased. The treatment of hepatocytes with IL-6 induced both hepcidin mRNA expression and hepcidin secretion. Conclusions Systemic inflammation induced by periodontitis leads to an increased risk for AI. IL-6-induced hepcidin could play a central mediator role and act as a key pathologic mechanism. Our results demonstrate periodontitis may be considered as an additional inflammatory disease contributing to the development of AI.

The impact of use of sodium-glucose transporter 2 (SGLT2) inhibitors on occurrence of various kinds of respiratory disorders has not been established. We aimed at evaluating the relationship between use of SGLT2 inhibitors and occurrence of 9 kinds of noninfectious respiratory disorders. Large randomized controlled trials (RCTs) of SGLT2 inhibitors were included in this study. We conducted fixed-effects meta-analysis to synthesize risk ratios (RRs) and 95% confidence intervals (CIs). We did subgroup analysis respectively stratified by type of underlying diseases and type of SGLT2 inhibitors. Nine Large RCTs were included for analysis. Compared with placebo, SGLT2 inhibitors significantly reduced the occurrence of overall respiratory disorders (RR 0.75, 95% CI 0.62–0.91), acute pulmonary oedema (RR 0.51, 95% CI 0.29–0.88), asthma (RR 0.57, 95% CI 0.33–0.995), and sleep apnoea syndrome (RR 0.35, 95% CI 0.12–0.99). SGLT2 inhibitors showed the reduced trends in the risks of chronic obstructive pulmonary disease (COPD) (RR 0.79, 95% CI 0.61–1.02; P = 0.073) and pulmonary hypertension (RR 0.43, 95% CI 0.16–1.17; P = 0.098). SGLT2 inhibitors had no significant effects on three other respiratory disorders. These effects exhibited by SGLT2 inhibitors were consistent across different underlying diseases (Psubgroup ≥0.209) and different SGLT2 inhibitors (Psubgroup ≥0.192). SGLT2 inhibitors can significantly reduce the occurrence of acute pulmonary oedema, asthma, and sleep apnoea syndrome; and produce the reduced trends in the risks of COPD and pulmonary hypertension. These findings will prompt further investigation on SGLT2 inhibitors for primary and secondary prevention of various respiratory disorders.

PurposeTo assess and describe patient-reported outcomes (PROs) in women with locally advanced/unresectable or metastatic breast cancer (aBC/mBC) with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 −) status receiving palbociclib combination therapy in a US real-world setting.MethodsA prospective, noninterventional, multicenter longitudinal study was conducted in US patients initiating treatment with palbociclib combination therapy for HR + /HER2 − aBC/mBC. PRO data (SF-12; CES-D-10; mood; pain; fatigue; interference of aBC/mBC or its treatment on family life, social life, physical activity, energy, and productivity; overall health rating; and quality of life [QOL]) were collected via a custom-developed mobile application at daily, weekly, and cycle-based intervals. Patient medical information (demographics, clinical characteristics, treatment information, and adverse events) was collected from medical records at baseline and at the end of the 6-month follow-up period.ResultsPatients’ general health status (SF-12) remained consistent throughout treatment and was generally consistent with published norms for individuals diagnosed with cancer. The presence of depression (CES-D-10) was low and did not change substantially over time. Mean pain and fatigue scores using an 11-point numeric rating scale were low and remained stable. Patients, on average, reported neutral or positive moods. Patient-reported QOL and overall health was primarily “Good,” “Very good,” or “Excellent.” Findings were consistent regardless of patient experience with neutropenia.ConclusionsPatients treated with palbociclib, on average, reported consistently low levels of pain and fatigue as well as good QOL and overall health that remained stable throughout the first 6 months of treatment regardless of episodes of neutropenia.

Spotted fever group rickettsiae, mainly maintained and transmitted by ticks, are important etiological agents of (re)emerging zoonotic diseases worldwide. It is of great significance to investigate spotted fever group rickettsiae in ticks in different areas for the prevention and control of rickettsioses. In this study, a total of 305 ticks were collected from wild and domestic animals in Chongqing, Guizhou, Yunnan, and Guangxi provinces of southwestern China during 2017–2019 and examined for the presence of spotted fever group rickettsiae by PCR with primers targeting the partial gltA, ompA, rrs, and htrA genes. Results showed that two spotted fever group rickettsiae species, including the pathogenic Candidatus Rickettsia jingxinensis (Rickettsiales: Rickettsiaceae) and a potential novel species Rickettsia sp. sw (Rickettsiales: Rickettsiaceae), were identified. The Ca. R. jingxinensis sequences were recovered from Rhipicephalus microplus (Ixodida: Ixodidae) and Haemaphysalis longicornis (Ixodida: Ixodidae) ticks and phylogenetically clustered with previous Ca. R. jingxinensis, Ca. R. longicornii (Rickettsiales: Rickettsiaceae), and Rickettsia sp. XY118 (Rickettsiales: Rickettsiaceae) strains. Rickettsia sp. sw was detected in Amblyomma geoemydae (Ixodida: Ixodidae) and Rh. microplus. Interestingly, as far as we know, this was the first report of Rickettsia (Rickettsiales: Rickettsiaceae) in A. geoemydae. Phylogenetic analyses indicated that this potential novel species was closely related to R. aeschlimannii (Rickettsiales: Rickettsiaceae) with gltA and ompA genes and grouped in a cluster composed of R. montanensis (Rickettsiales: Rickettsiaceae), R. raoultii (Rickettsiales: Rickettsiaceae), R. aeschlimannii, R. massiliae (Rickettsiales: Rickettsiaceae), and R. rhipicephali (Rickettsiales: Rickettsiaceae) with htrA, while formed a separate clade with rrs. The pathogenicity of Rickettsia sp. sw should be further confirmed. These results expand the knowledge of the geographical distribution and vector distribution of spotted fever group rickettsiae in China and are useful for assessing the potential public health risk.

Background: Palbociclib is a selective cyclin-dependent kinase (CDK) 4/6 inhibitor used in combination with aromatase inhibitors or fulvestrant for patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer (ABC/MBC). Palbociclib was the first CDK 4/6 inhibitor approved for HR+/HER2&minus, ABC/MBC treatment in Canada in combination with letrozole (P+L) as an initial endocrine-based therapy (approved March 2016), or with fulvestrant (P+F) following disease progression after prior endocrine therapy (approved May 2017). The Ibrance Real World Insights (IRIS) study (NCT03159195) collected real-world outcomes data for palbociclib-treated patients in several countries, including Canada. Methods: This retrospective chart review included women with HR+/HER2&minus, ABC/MBC receiving P+L or P+F in Canada. Physicians reviewed medical records for up to 14 patients, abstracting demographic and clinical characteristics, treatment patterns, and clinical outcomes. Progression-free rates (PFRs) and survival rates (SRs) at 6, 12, 18, and 24 months were estimated via Kaplan&ndash, Meier analysis. Results: Thirty-three physicians examined medical records for 247 patients (P+L, n = 214, P+F, n = 33). Median follow-up was 8.8 months for P+L and 7.0 months for P+F. Most patients were initiated on palbociclib 125 mg/d (P+L, 90.2%, P+F, 84.8%). Doses were reduced in 16.6% of P+L and 14.3% of P+F patients initiating palbociclib at 125 mg/d. The PFR for P+L was 90.3% at 12 months and 78.2% at 18 months, corresponding SRs were 95.6% and 93.0%. For P+F, 6-month PFR was 91.0%, 12-month SR was 100.0%. Conclusions: Dose reduction rates were low and PFR and SR were high in this Canadian real-world assessment of P+L and P+F treatments, suggesting that palbociclib combinations are well tolerated and effective.

IntroductionThe staphylococcal enterotoxin C (SEC), a commercially available bio-product from Staphylococcus aureus (S. aureus), has been widely used to control MPE.ObjectivesWe designed and performed a new systematic review (SR) and meta-analysis to clarify the perfusion protocols with SEC, determine their clinical effectiveness and safety, and reveal the indication and optimum usage for achieving the desired responses.MethodologyAll randomized controlled trials (RCTs) about SEC for MPE were collected from electronic databases (from inception until July 2021), and clustered into multiple logical topics. After evaluating their methodological quality, we pooled the data from each topic using the meta-analysis or descriptive analysis, and summarized the evidence quality using the grading of recommendation assessment, development, and evaluation (GRADE) approach.ResultsAll 114 studies were clustered into SEC perfusion alone or plus chemical agents. The SEC alone showed a better complete response (CR), a lower pleurodesis failure, and adverse drug reactions (ADRs), and a higher fever than cisplatin (DDP) alone. The SEC and chemical agents developed 10 perfusion protocols. Among them, only SEC and DDP perfusion showed a better CR, a lower failure, disease progression and ADRs, and a higher fever than DDP alone. The SEC (100–200 ng per time, one time a week for one to four times) with DDP (30–40 mg, or 50–60 mg each time) significantly improved clinical responses for patients with moderate to large volume, Karnofsky performance status (KPS) scores ≥40, ≥50, or ≥60, and anticipated survival time (AST) ≥2 or 3 months. Most results were moderate to low quality.ConclusionCurrent pieces of evidence indicate that super-antigen SEC is a pleurodesis agent, which provides an attractive alternative to existing palliative modalities for patients with MPE. Among 10 protocols, the SEC and DDP perfusion is a most commonly used, which shows a significant improvement in clinical responses with low ADRs. These findings also provide a possible indication and optimal usage for SEC and DDP perfusion.

In situ fragmentation bioleaching is a promising way to perform deep mining safely, economically, and in an environmentally friendly manner, where oxygen plays a critical role in microbial growth and mineral dissolution. However, the lack of oxygen limits the implementation of in-situ fragmentation bioleaching. To overcome this limitation, aeration was proposed, with saturated dissolved oxygen concentration as an important indicator. Orthogonal experiments were conducted to measure saturated dissolved oxygen concentration at various temperature, pH, and electrolyte (ferrous sulfate, ferric sulfate, copper sulfate, and sulfuric acid) concentration conditions. Experimental data were analyzed by Python programming language and least squares method to obtain a saturated dissolved oxygen concentration model. Results showed that temperature had the most significant effect on oxygen solubility, which was concluded by comparing the results of surface fitting based on the least squares method. At 30–40°C, the saturated dissolved oxygen concentration decreased faster as metal ions concentration increased. The conjoint effect of the five variables on oxygen solubility showed that pH was linearly negatively related to oxygen solubility. Additionally, a mathematical model was also proposed to predict the saturated dissolved oxygen concentration in in situ fragmentation bioleaching of copper sulfide ores. This work enables bioleaching processes to be modeled and controlled more effectively.

New finite strain elastoplastic $$J_2$$ -flow equations with no reference to the yield condition are proposed for the purpose of simultaneously simulating low-to-ultrahigh cycle failure effects of metals. As inherent response features of such new equations, the entire responses up to eventual failure under cyclic and non-cyclic loadings of constant and variable amplitudes are automatically predicted, in a direct sense without involving any additional damage-like variables and any ad hoc failure criteria. The thermodynamic consistency is ensured by demonstrating that the intrinsic dissipation is identically non-negative. Furthermore, a high-efficiency algorithm for integrating the elastoplastic rate equations is established toward bypassing very time-consuming numerical procedures in treating cyclic responses with high and even ultrahigh cycle number. With numerical examples, model predictions are shown to be in good agreement with fatigue failure data for low, high and very high cycle numbers, and the new algorithm is shown to be much faster and far more efficient than usual integration procedures.

A new finite strain elatoplastic J2-flow model with coupling effects of both isotropic and anisotropic hardening is proposed with the co-rotational logarithmic rate. In terms of certain single-variable shape functions representing uniaxial loading and unloading curves, explicit multi-axial expressions for the three hardening quantities incorporated in the new model proposed are derived in unified forms for the purpose of automatically and accurately simulating complex pseudoelastic-to-plastic transition effects of shape memory alloys (SMAs) under multiple loading-unloading cycles. Numerical examples show that with only a single parameter of direct physical meaning for each cycle, accurate and explicit simulations may be achieved for extensive data from multiple cycle tests.

A new finite strain elastoplastic $$J_{\mathrm {2}}$$ -flow model is established with an explicit formulation of work-hardening and softening effects up to eventual failure, in which both a new flow rule free of yielding and an asymptotically vanishing stress limit are incorporated. The novelties of this new model are as follows: (i) Fatigue failure effects under repeated loading conditions with either constant or varying amplitudes are automatically characterized as inherent response features; (ii) neither additional damage-like variables nor failure criteria need to be involved; and (iii) both high- and low-cycle fatigue effects may be simultaneously treated. A fast and efficient algorithm of high accuracy is proposed for directly simulating high- and medium–high-cycle fatigue failure effects under repeated loading conditions. Toward this goal, a direct and explicit relationship between the fatigue life and the stress amplitude is obtained by means of explicit and direct procedures of integrating the coupled elastoplastic rate equations for any given number of loading–unloading cycles with varying stress amplitudes. Numerical examples suggest that the new algorithm is much more fast and efficient than usual tedious and very time-consuming integration procedures.

Swertia mussotii Franch. has been widely used in Tibetan folk medicine as an important drug ingredient for the treatment of hepatitis and hepatobiliary disease and for homeopathic purposes. But the lacking natural resources of S. mussotii is becoming more obvious with increasing market demands. The main objective of this work was to examine genetic differentiation among S. mussotii populations from different geographical locations and use the knowledge gained to facilitate future selection of the species suitable for large-scale cultivation to meet the increasing demand for medicinal use of this plant. In this study, 68 S. mussotii Franch samples collected from Zhongda (16), Chengduo (16), and Xiewu (8) County in Qinghai Province, Xiaojin (14) and Jinchuan (14) County in Sichuan Province, China and 4 samples from related species, were genotyped using genotyping-by-sequencing (GBS) technique. GBS scored 4095 SNPs with a minor-allele frequency > 0.25 and an average read depth

New finite elastoplastic J2-flow equations are proposed for the purpose of explicitly simulating continuous transitions from plastic to pseudo-elastic effects of SMAs under multiple loading-unloading cycles. Novelties of such models are as follows: (i) New hardening effects are incorporated by introducing interplay between the changing of the yield surface radius and the moving of the yield surface center; (ii) extensive experimental data may be accurately simulated for any given number of loading-unloading cycles; (iii) the complicated task for simulating extensive data may be accomplished by independently fitting certain single-variable functions; and (iv) such single-variable functions may be presented in explicit forms for the purpose of automatically, accurately fitting extensive data, thus bypassing uncertainties and undue complexities usually involved in iteratively solving a coupled system of nonlinear constitutive rate equations toward identifying numerous unknown parameters. Numerical examples for model validation are presented and in good agreement with stress-strain data up to 20 loading-unloading cycles given in literature.

Background: Palbociclib in combination with letrozole (P+L) was the first cyclin-dependent-kinase 4/6 inhibitor approved in the U.S for treatment of metastatic breast cancer (mBC). Per the U.S. label, the recommended starting dose for Palbociclib (P) is 125 mg and patients should have complete blood count (CBC) monitoring prior to the start of treatment, at the beginning of each cycle, on day 15 of the first 2 cycles, and as clinically indicated. We sought to evaluate adherence to these FDA label in patients receiving P+L as initial endocrine-based therapy. Methods: Adult post-menopausal women with metastatic HR+/HER2- breast cancer who initiated P+L on or after 02/03/2015 were randomly identified by providers in the Cardinal Health Oncology Provider Extended Network (OPEN), which includes over 7,000 US oncologists/hematologists. Providers who were part of OPEN who responded to an initial feasibility request (survey) indicating an interest to participate in the study and treating the patients of interest were invited to participate. Providers were asked to randomly select eligible patients treated with P+L who were initiated on first-line P+L at least 3 months following their first treatment of any patient with P+L. Providers were asked to indicate that the patient had been randomly selected from among all eligible patients and were able to enter up to 10 total patients. All data were abstracted by the patient's treating provider in an electronic case report form (eCRF). Providers abstracted data related to patient characteristics, dosing, and frequency of CBC monitoring in the 30 days prior to and during the first 2 cycles of therapy of randomly selected patients from the time of initiation of P+L through Feb 2019 (or end of follow up/death). Providers completed data validation by re-entering select data from randomly selected patients (10% of the total sample) and for patients which were flagged for quality control review by Cardinal Health clinical research staff and data analytics team members when the results were inconsistent or deviated from the population averages. Results: Thirty-one providers submitted 202 eCRFs, of which 193 were eligible (9 patients removed with non-verifiable data). Demographics: mean age was 65.0 y/o (SD = 10.5), 74.6% white, 38.6% commercially insured. Clinical characteristics: 65.8% de novo metastatic, 51.3% visceral disease at initiation of P+L, 25.4% bone only disease, 10.4% ECOG-PS ≥2. Median follow-up from P+L initiation was 15.4 months, 45.6% of patients had discontinued P+L at data cut-off. Overall, 86.0%, 13.5%, and 0.5% of patients initiated treatment of P at the 125 mg, 100 mg, and 75mg dose, respectively. Dose reductions were reported in 17.1% of patients. CBC testing was conducted prior to P+L initiation in 99.0% of patients; median number of CBC tests during cycle 1 was 2.0; 37% of patients had only one CBC test. In cycle 2, median number of CBC tests was 1.5 and 46.5% of patients had only one CBC test. Conclusions: Physicians were generally compliant with the Palbociclib package insert recommendations for dosing and monitoring during the first cycle, less so for monitoring during the second cycle in women with HR+/HER2- mBC. Funding: Pfizer Inc. Citation Format: Jonathan Kish, Talia Miller, Damion Nero, Djibril Liassou, Xianchen Liu, Lynn McRoy, Bruce Feinberg, Lin Zhan, Jeffrey Trocio. Real-world dosing and CBC monitoring in patients with metastatic breast cancer during palbociclib plus letrozole therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-13.

Background: MADELINE is an observational, multicenter study of women in the United States with advanced/metastatic breast cancer (ABC/MBC) receiving palbociclib in combination with either an aromatase inhibitor (AI) as initial endocrine therapy or fulvestrant after progression on prior endocrine therapy. A novel mobile application was used to collect real-time patient-reported outcome (PRO) data to assess patient functioning and quality of life through daily, weekly, and monthly questionnaires for 6 months. Methods: Patients completed the Center for Epidemiologic Studies Depression Scale (CES-D-10) at each cycle; total scores range from 0 to 30, where 10 or more is considered to indicate depression. Based on CES-D-10 scores patients’ depression status could vary cycle-to-cycle. Data on patient’s mood was collected using a daily seven-level mood rating (“very sad” to “most happy”) and a weekly five-level question on breast cancer or its treatment’s negative effect on mood or emotions (“not at all” to “a great deal”). A descriptive analysis examining the relationship between depression (CES-D-10), and the two mood questions was conducted among patients with a completed baseline electronic case report form and relevant mobile app data as of May 1, 2019. Results: Twenty-three sites contributed 137 patients (median [range] age 60 [34, 82]; white: 84%; ECOG 0-1: 87%; initiated palbociclib plus AI at enrollment: 62%). At cycle 1, 48 patients were classified as without depression (score 10). During week 1 of cycle 1, the average percentage of days where patients without depression reported a mood of “Neutral” was 37.8%, “Content” was 34.8%, and “Happy” was 22.9% compared to patients with depression reporting 55.2% for “Neutral”, 21.6% for “Content”, and 2.6% for “Happy”. In the same reporting period, 56% (15/27), 19% (5/27), and 4% (1/27) of patients with depression indicated breast cancer or its treatment had negatively impacted their mood or emotions “moderately”, “quite a bit”, or “a great deal” respectively whereas 13% (5/38) of patients without depression indicated it negatively impacted their mood or emotions “moderately” and 0% indicated either “quite a bit” or “a great deal”. Results were relatively similar across the cycles overall and for patients that initiated either palbociclib plus AI or palbociclib plus fulvestrant. Conclusions: The majority of patients in the MADELINE study did not report symptoms indicating depression based on the CES-D-10 at the beginning of treatment and across cycles. Results suggest that the mood and emotions of patients with depression was more negatively impacted by breast cancer or its treatment compared with patients without depression. Citation Format: David Richardson, Lin Zhan, Maria Reynolds, Dawn Odom, Lynn McRoy, Debanjali Mitra, Jeffrey Hargis. Relationship between depression status and daily and weekly mood in the MADELINE study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-41.

Background: MADELINE is an observational, multicenter study of women in the United States with metastatic breast cancer (MBC) receiving palbociclib in combination with an aromatase inhibitor (AI) as initial endocrine therapy, or fulvestrant after progression on prior endocrine therapy. A novel mobile application is used to collect real-time patient-reported outcome (PRO) data to assess patient functioning and quality of life through daily, weekly, and monthly questionnaires for 6 months. Methods: An interim analysis of select PRO data was conducted among completed and ongoing patients with a minimum of baseline mobile app and eCRF data as of May 1, 2019. PROs analyzed included daily assessments of seven-level mood rating (very sad to most happy), pain and fatigue severity measured using an 11-point (0 to 10 with 10 being the worst possible pain or fatigue) numeric rating scale (NRS), and pain location. Analyses were descriptive and daily data were averaged to create weekly scores. Results: Twenty-three sites contributed 137 patients (mean [± standard deviation] age 59.7 ± 11.74; white: 84%; ECOG 0-1: 87%; initiated palbociclib plus AI at enrollment: 62%). At the start of cycle 1, the average percentage of days where patients reported a mood of “Neutral” was 44.5%, followed by “Content” with 26.5%; results were relatively stable across the study. The average daily level of pain was 2.3 (2.32) on the NRS during cycle 1, week 1 with no substantial numerical changes across the study [cycle 6, week 4: mean± standard deviation 2.0 (2.13)]. Pain was indicated throughout the body but reported more frequently in the lower body, legs and chest. The average daily fatigue severity on the NRS during the following time points were [mean ± standard deviation]: cycle 1, week 1: 2.8 (2.25); cycle 3, week 1: 2.5 (2.31); and cycle 6, week 1: 2.3 (1.91). Results were relatively similar for patients that initiated either palbociclib plus AI or palbociclib plus fulvestrant. Average daily pain and fatigue scores for week 1 by cycle are shown in the table. Conclusions: Daily reported PRO collected in the MADELINE study suggest a low level of pain and fatigue that does not change substantially over time. The most commonly reported mood ratings among patients were neutral or content. Average daily pain and fatigue scores by cyclePalbociclib + AI(N = 85)Palbociclib + Fulvestrant(N = 52)Overall(N = 137)nMean (SD) scorenMean (SD) scorenMean (SD) scoreCycle 1/Week 1Pain842.4 (2.41)462.0 (2.16)1302.3 (2.32)Fatigue842.7 (2.31)462.9 (2.16)1302.8 (2.25)Cycle 2/Week 1Pain691.9 (2.15)411.7 (2.09)1101.8 (2.12)Fatigue692.4 (2.34)412.6 (2.37)1102.5 (2.34)Cycle 3/Week 1Pain621.9 (2.18)341.4 (1.79)961.7 (2.05)Fatigue622.6 (2.33)352.3 (2.28)972.5 (2.31)Cycle 4/Week 1Pain562.1 (2.23)271.8 (2.45)832.0 (2.29)Fatigue562.6 (2.45)272.3 (2.35)832.5 (2.41)Cycle 5/Week 1Pain491.7 (1.89)211.5 (1.78)701.7 (1.85)Fatigue492.4 (2.19)212.1 (2.03)702.3 (2.13)Cycle 6/Week 1Pain381.7 (1.97)151.8 (2.17)531.7 (2.01)Fatigue382.3 (1.89)152.6 (2.00)532.3 (1.91) Citation Format: David Richardson, Lin Zhan, Maria Reynolds, Kelly Hollis, Lynn McRoy, Debanjali Mitra, Reshma Mahtani. Trends in daily mood, pain, and fatigue among participants in the MADELINE study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-35.

Finite strain elastoplastic J2-flow equations are established toward the purpose of automatically, accurately simulating pseudo-elastic effects of SMAs. The uniaxial responses derived from these equations in each loading-unloading cycle exactly produce a closed stress-strain curve of any given shape. Then, any given test data for pseudo-elastic hysteresis loops of SMAs may be accurately fitted by means of a new technique for combining linear spline functions into a unified, smooth interpolating function, in a sense with no need to identify any unknown parameters.

The increasing prevalence and expanding distribution of tick-borne viruses globally have raised health concerns, but the full repertoire of the tick virome has not been assessed. We sequenced the meta-transcriptomes of 31 different tick species in the Ixodidae and Argasidae families from across mainland China, and identified 724 RNA viruses with distinctive virome compositions among genera. A total of 1,801 assembled and complete or nearly complete viral genomes revealed an extensive diversity of genome architectures of tick-associated viruses, highlighting ticks as a reservoir of RNA viruses. We examined the phylogenies of different virus families to investigate virome evolution and found that the most diverse tick-associated viruses are positive-strand RNA virus families that demonstrate more ancient divergence than other arboviruses. Tick-specific viruses are often associated with only a few tick species, whereas virus clades that can infect vertebrates are found in a wider range of tick species. We hypothesize that tick viruses can exhibit both 'specialist' and 'generalist' evolutionary trends. We hope that our virome dataset will enable much-needed research on vertebrate-pathogenic tick-associated viruses.

Background: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly emerged virus that possesses a great threat to human health because of the high fatality rate. Method: To develop sensitive and specific sero-diagnosis systems for SFTSV infections, monoclonal antibodies (MAbs) against recombinant SFTSV nucleocapsid (rSFTSV-N) protein were developed by immunizing BALB/C mice with rSFTSV-N protein and fusing the spleen cells with SP2/0 myeloma cells. Three hybridoma cell lines secreting MAbs against rSFTSV-N were obtained. MAb based IgG sandwich enzyme linked immunosorbent assay (ELISA) and IgM capture ELISA systems were established by using the newly developed MAbs. One hundred fifteen clinical suspected SFTS patient serum samples were used to evaluate the newly established systems by comparing with the total antibody detecting sandwich ELISA system and indirect ELISA systems. Results: The MAb based sandwich IgG ELISA was perfectly matched with that of the total antibody sandwich ELISA and the indirect IgG ELISA with a sensitivity and specificity of 100%. IgM capture ELISA results perfectly matched with that of the total antibody sandwich ELISA while was more sensitive comparing with the indirect IgM ELISA. Conclusions: The MAbs against rSFTSV-N protein offer new tools for SFTSV studies and our newly developed MAb-based IgG and IgM capture ELISA systems would offer safe and useful tools for diagnosis of SFTS virus infections and epidemiological investigations.

To investigate the characteristics ofTwenty-one patients with multiple myeloma secondary extramedullary infiltration confirmed by pathology or follow-up from January 2012 to October 2020 in the First Affiliated Hospital of University of Science and Technology of China were retrospectively analyzed. All the patients underwentTwenty-one patients included 12 males and 9 females, aged from 41 to 77 years old, with an average of 58.3±10.0; 9 cases of extramedullary infiltration involving lymph nodes; lung, stomach, spleen, and kidney were involved respectively in 2 cases; retroperitoneal, right auricle, subcutaneous nodule, and spinal meninges involvement were reported in each one case respectively. The maximum SUVmax value of extra-medullary lesions was 21.2, the minimum value was 2.1, and mean was 7.7±5.3. The maximum SUVmax value of bone marrow was 33.5, the minimum was 2.4, and mean was 6.6±3.6. There was no statistically significant difference in SUVmax value between extra-medullary lesions and bone marrow (Z=-1.195, P=0.232).探讨多发性骨髓瘤继发髓外浸润的回顾性分析2012年1月至2020年10月中国科学技术大学附属第一医院21例为穿刺病理或随访证实的多发性骨髓瘤继发髓外浸润患者，所有患者治疗前均行21例患者中，男12例，女9例，年龄41-77岁，平均（58.3±10.0）岁；骨髓外浸润累及淋巴结9例，肺、胃、脾脏及肾脏各2例，腹膜后、右心耳、皮下结节及脊膜受累及各1例；髓外浸润SUVmax最大值21.2，最小值2.1，平均值7.7±5.3，骨髓病变最大值33.5，最小值2.4，平均值6.6±3.6，髓外浸润与骨髓病变SUVmax比较，二者之间差异无统计学意义（Z=-1.195，P=0.232）.

The incidence of breast cancer is rising in Japan, particularly in postmenopausal women. The CDK 4/6 inhibitor palbociclib has demonstrated efficacy in clinical studies in patients with hormone receptor-positive (HR+), human epidermal growth factor 2 (HER2)-negative advanced/metastatic breast cancer (ABC/MBC). The Ibrance Real World Insights (IRIS) study (NCT03159195) collected real-world data for palbociclib-treated patients in several countries including Japan, where such data are currently scarce.IRIS was a retrospective chart review study of patients with confirmed HR+/HER2- ABC/MBC receiving palbociclib according to approved indications in real-world clinical practice. In Japan, physicians each abstracted data from patient medical records for up to eight sequential patients treated with palbociclib plus an aromatase inhibitor (P+AI) or fulvestrant (P+F). Outcomes included progression-free rates (PFRs) and survival rates (SRs).Fifty-eight physicians abstracted data for 170 patients receiving palbociclib in the first (64.1%) or second or later line (35.9%), in combination with AI (51.2%) or fulvestrant (48.8%). Median follow-up was 10.4 months. Most patients were initiated on palbociclib 125 mg/d (P+AI, 63.2%; P+F, 78.3%). PFRs at 12 and 24 months were 76.2% and 52.6%, respectively, for P+AI and 71.6% and 65.6%, respectively for P+F. PFRs at 12 and 24 months were 85.4% and 66.5%, respectively, for first-line palbociclib combinations and 56.4% and 50.7%, respectively, for second- or later-line palbociclib combinations.In this analysis of the Japanese IRIS cohort, outcomes in terms of PFRs and SRs appear to be better with first- versus second or later-line palbociclib, regardless of the endocrine partner.

Recently, Lin and colleagues assessed the safety of sodium-glucose cotransporter 2 inhibitors (SGLT2is) by a meta-analysis [1], in which the authors assessed 16 kinds of adverse events (AE) reported in the published articles based on 10 randomized controlled trials. We conducted a further meta-analysis and targeted the association between use of SGLT2is and occurrences of various kinds of serious AE published in the Clinical Trials website (clinicaltrials.gov). Our meta-analysis revealed that use of SGLT2is was not significantly associated with occurrences of 980 kinds of serious AE but was significantly associated with lower risks of 29 kinds of serious AE, especially including several important respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease, sleep apnoea syndrome, and pneumonia). These findings may cause more studies to evaluate the possibilities of gliflozins being used for prevention of these specific diseases.