Chemoresistance is the major obstacle in multiple myeloma (MM) management. We previously showed that macrophages protect myeloma cells, on a cell contact basis, from melphalan or ...dexamethasone-induced apoptosis in vitro. In this study, we found that macrophage-mediated myeloma drug resistance was also seen with purified macrophages from myeloma patients' bone marrow (BM) in vitro and was confirmed in vivo using the human myeloma-SCID (severe combined immunodeficient) mouse model. By profiling differentially regulated and paired plasma membrane protein genes, we showed that PSGL-1 (P-selectin glycoprotein ligand-1)/selectins and ICAM-1/CD18 played an important role in macrophage-mediated myeloma cell drug resistance, as blocking antibodies against these molecules or genetic knockdown of PSGL-1 or ICAM-1 in myeloma cells repressed macrophages' ability to protect myeloma cells. Interaction of macrophages and myeloma cells via these molecules activated Src and Erk1/2 kinases and c-myc pathways and suppressed caspase activation induced by chemotherapy drugs. Thus, our study sheds new light on the mechanism of drug resistance in MM and provides novel targets for improving the efficacy of chemotherapy in patients.
In this paper, the factors of safety and critical slip surfaces obtained by the limit equilibrium method (LEM) and two finite element methods (the enhanced limit strength method (ELSM) and strength ...reduction method (SRM)) are compared. Several representative two-dimensional slope examples are analysed. Using the associated flow rule, the results showed that the two finite element methods were generally in good agreement and that the LEM yielded a slightly lower factor of safety than the two finite element methods did. Moreover, a key condition regarding the stress field is shown to be necessary for ELSM analysis.
Primary aldosteronism (PA) diagnosis is affected by antihypertensive drugs that are commonly taken by patients with suspected PA. In this study, we developed and validated a diagnostic model for ...screening PA without drug washout.
We retrospectively analyzed 1095 patients diagnosed with PA or essential hypertension. Patients were randomly grouped into training and validation sets at a 7:3 ratio. Baseline characteristics, plasma aldosterone concentration (PAC), and direct renin concentration (DRC) before and after drug washout were separately recorded, and the aldosterone-to-renin ratio (ARR) was calculated.
PAC and ARR were higher and direct renin concentration was lower in patients with PA than in patients with essential hypertension. Furthermore, the differences in blood potassium and sodium concentrations and hypertension grades between the two groups were significant. Using the abbreviations potassium (P), ARR (A), PAC (P), sodium (S), and hypertension grade 3 (3), the model was named PAPS
. The PAPS
model had a maximum score of 10, with the cutoff value assigned as 5.5; it showed high sensitivity and specificity for screening PA in patients who exhibit difficulty in tolerating drug washout.
PA screening remains crucial, and standard guidelines should be followed for patients to tolerate washout. The PAPS
model offers an alternative to minimize risks and enhance diagnostic efficiency in PA for those facing washout challenges. Despite its high accuracy, further validation of this model is warranted through large-scale clinical studies.
A
bstract
Using data samples with an integrated luminosity of 6
.
4 fb
−
1
collected by the BESIII detector operating at the BEPCII storage ring, the process of
e
+
e
−
→
γϕJ/ψ
is studied. The ...processes of
e
+
e
−
→
ϕχ
c
1
,
c
2
,
χ
c
1
,
c
2
→
γJ/ψ
are observed with a significance of more than 10
σ
. The
s
-dependent cross section of
e
+
e
−
→
ϕχ
c
1
,
c
2
is measured between 4.600 and 4.951 GeV, and evidence of a resonance structure is found for the first time in the
ϕχ
c
2
process. We also search for the processes of
e
+
e
−
→
γX
(4140),
γX
(4274) and
γX
(4500) via the
γϕJ/ψ
final state, but no obvious structures are found. The upper limits on the production cross section times the branching fraction for these processes at the 90% confidence level are reported.
By analyzing e(+)e(-) annihilation data with an integrated luminosity of 2.93 fb(-1) collected at the center-of-mass energy root s = 3.773 GeV with the BESIII detector, we present the first absolute ...measurements of the branching fractions of twenty Cabibbo-suppressed hadronic D0(+) decays involving multiple pions. The highest four branching fractions obtained are B(D-0 -> pi(+)pi(-)pi(0)) = (1.343 +/- 0.013(stat) +/- 0.016(syst))%, B(D-0 -> pi(+)pi(-)2 pi(0)) = (1.002 +/- 0.019(stat )+/- 0.024(syst))%, B(D-0 -> 2 pi(+)pi(-)pi(0))=(1.165 +/- 0.021(stat) +/- 0.021(sy)(st))%, and B(D+ -> 2 pi(+)pi(-)pi(0)). (1.074 +/- 0.040(stat) 0.030(syst))%. The CP asymmetries for the six decays with highest signal yields are also determined and found to be compatible with zero.
In this study, we assess global hydropower potential using runoff and stream flow data, along with turbine technology performance, cost assumptions, and consideration of protected areas. The results ...provide the first comprehensive quantification of global hydropower potential including gross, technical, economic, and exploitable estimates. Total global potential of gross, technical, economic, and exploitable hydropower are estimated to be approximately 128, 26, 21, and 16 petawatt hours per year, respectively. The economic and exploitable potential of hydropower are calculated at less than 9 cents per kW h. We find that hydropower has the potential to supply a significant portion of world energy needs, although this potential varies substantially by region. Globally, exploitable hydropower potential is comparable to total electricity demand in 2005. Hydropower plays different roles in each country owing to regional variation in potential relative to electricity demand. In some countries such as the Congo, there is sufficient hydropower potential (>10 times) to meet all electricity demands, while in other countries such as United Kingdom, hydropower potential can only accommodate a small portion (<3%) of total demand. A sensitivity analysis indicates that hydropower estimates are sensitive to a number of parameters: design flow (varying by −10% to +0% at less than 9 cents per kW h), cost assumptions (by −35% to +12%), turbine efficiency (by −40% to +20%), stream flow (by −35% to +35%), fixed charge rate (by −15% to 10%), and protected land (by −15% to 20%). This sensitivity analysis emphasizes the reliable role of hydropower for future energy systems, when compared to other renewable energy resources with larger uncertainty in their future potentials.
This study provides the first comprehensive quantification of global hydropower potential including gross, technical, economic, and exploitable estimates.
Purpose
Achieving a pathologic complete response (pCR) with neoadjuvant therapy for HER2-positive breast cancer is associated with less recurrence and improved clinical outcomes compared to having ...residual cancer at surgery. However, recent data have demonstrated favorable outcomes for patients with residual HER2-positive cancer who received adjuvant trastuzumab emtansine (TDM-1). Therefore, we sought to determine the optimal chemotherapy/anti-HER2 treatment strategy.
Methods
We created a decision-analytic model for patients with stage II–III HER2-positive cancer that incorporated utilities based on toxicity and recurrence. We separately modeled hormone receptor-negative (HR−) and positive (HR+) disease and calculated quality-adjusted life years (QALYs) and costs through 5 years. Simulated patients received one of the following neoadjuvant treatments: three ‘intensive’ regimens (TCHP: docetaxel, carboplatin, trastuzumab, pertuzumab; THP + AC: taxol, trastuzumab, pertuzumab then doxorubicin and cyclophosphamide; THP: taxol, trastuzumab, pertuzumab) and two ‘de-escalated’ regimens (TH: taxol, trastuzumab; TDM-1) followed by adjuvant treatment based on pathologic response.
Results
Among ‘intensive’ neoadjuvant strategies, treatment with THP was more effective and less costly than TCHP or THP + AC. When ‘de-escalated’ strategies were included, TH became the most cost-effective. For HR-negative cancer, TH had 0.003 fewer quality-adjusted life years (QALYs) than THP but was less costly by $55,831, resulting in an incremental cost-effectiveness ratio of over $18M/QALY for THP, well above any threshold. For HR-positive cancer, neoadjuvant TH dominated the THP strategy.
Conclusion
An adaptive-treatment strategy beginning with neoadjuvant THP or TH followed by tailoring post-operative therapy reduces treatment costs, and spares toxicity compared to more intensive chemotherapy regimens for women with HER2-positive breast cancer.
Using a data sample of ${e}^{+}{e}^{{-}}$ collisions corresponding to an integrated luminosity of $567\text{ }\text{ }{\mathrm{pb}}^{{-}1}$ collected at a center-of-mass energy of $\sqrt{s}=4.6\text{ ...}\text{ }\mathrm{GeV}$ with the BESIII detector, we measure the absolute branching fraction of the inclusive semileptonic ${\mathrm{{\Lambda}}}_{c}^{+}$ decay with a double-tag method. We obtain $\mathcal{B}({\mathrm{{\Lambda}}}_{c}^{+}{\rightarrow}X{e}^{+}{{\nu}}_{e})=(3.95\pm{}0.34\pm{}0.09)%$, where the first uncertainty is statistical and the second systematic. Using the known ${\mathrm{{\Lambda}}}_{c}^{+}$ lifetime and the charge-averaged semileptonic decay width of nonstrange charmed mesons (${D}^{0}$ and ${D}^{+}$), we obtain the ratio of the inclusive semileptonic decay widths $\mathrm{{\Gamma}}({\mathrm{{\Lambda}}}_{c}^{+}{\rightarrow}X{e}^{+}{{\nu}}_{e})/\overline{\mathrm{{\Gamma}}}(D{\rightarrow}X{e}^{+}{{\nu}}_{e})=1.26\pm{}0.12$.
A bstract The $$ {D}_s^{+}\to {K}^{+}{K}^{-}{\mu}^{+}{\nu}_{\mu } $$ D s + → K + K − μ + ν μ decay is studied based on 7.33 fb − 1 of e + e − collision data collected with the BESIII detector at ...center-of-mass energies in the range from 4.128 to 4.226 GeV. The absolute branching fraction is measured as $$ \mathcal{B}\left({D}_s^{+}\to \phi {\mu}^{+}{\nu}_{\mu}\right)=\left(2.25\pm 0.09\pm 0.07\right)\times {10}^{-2} $$ B D s + → ϕ μ + ν μ = 2.25 ± 0.09 ± 0.07 × 10 − 2 , the most precise measurement to date. Combining with the world average of $$ \mathcal{B}\left({D}_s^{+}\to \phi {e}^{+}{\nu}_e\right) $$ B D s + → ϕ e + ν e , the ratio of the branching fractions obtained is $$ \frac{\mathcal{B}\left({D}_s^{+}\to \phi {\mu}^{+}{\nu}_{\mu}\right)}{\mathcal{B}\left({D}_s^{+}\to \phi {e}^{+}{\nu}_e\right)}=0.94\pm 0.08 $$ B D s + → ϕ μ + ν μ B D s + → ϕ e + ν e = 0.94 ± 0.08 , in agreement with lepton universality. By performing a partial wave analysis, the hadronic form factor ratios at q 2 = 0 are extracted, finding $$ {r}_V=\frac{V(0)}{A_1(0)}=1.58\pm 0.17\pm 0.02 $$ r V = V 0 A 1 0 = 1.58 ± 0.17 ± 0.02 and $$ {r}_2=\frac{A_2(0)}{A_1(0)}=0.71\pm 0.14\pm 0.02 $$ r 2 = A 2 0 A 1 0 = 0.71 ± 0.14 ± 0.02 , where the first uncertainties are statistical and the second are systematic. No significant S -wave contribution from f 0 (980) → K + K − is found. The upper limit $$ \mathcal{B}\left({D}_s^{+}\to {f}_0(980){\mu}^{+}{\nu}_{\mu}\right)\cdot \mathcal{B}\left({f}_0(980)\to {K}^{+}{K}^{-}\right)<5.45\times {10}^{-4} $$ B D s + → f 0 980 μ + ν μ ⋅ B f 0 980 → K + K − < 5.45 × 10 − 4 is set at 90% credibility level.
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