Systemic Treatment for Advanced and Metastatic Non-Clear Cell Renal Cell Carcinoma: Examining Modern Therapeutic Strategies for a Notoriously Challenging Malignancy

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of malignancies that represents 25% of renal cell carcinoma (RCC) cases. Treatment for non-clear cell histologies is mostly based on evidence from small phase II clinical trials or extrapolated from successful therapies in clear cell RCC because of the low incidence of non-clear cell pathology. Advances in genomic profiling have improved clinicians’ understanding of molecular targets for nccRCC, such as altered mesenchymal epithelial transition (MET) gene status and fumarate hydratase (FH) gene inactivation, but patient outcomes remain poor and optimal management of this disease remains unclear. This review assesses outcomes by histologic subtype from 27 prospective and 13 ongoing clinical trials to identify therapeutic strategies for advanced or metastatic nccRCC. Vascular endothelial growth factor tyrosine kinase inhibitors (TKI), such as sunitinib, and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, have demonstrated efficacy and remain viable treatment options, with a preference for sunitinib. However, everolimus is preferred in patients with chromophobe RCC because folliculin (FLCN) gene mutations upregulate the mTOR pathway. Novel TKIs, such as cabozantinib, show improved outcomes in patients with papillary RCC because of targeted MET inhibition. Platinum-based chemotherapy continues to be the recommended treatment strategy for collecting duct and medullary RCC. Clinically meaningful antitumor activity has been observed across all non-clear cell histologies for immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and ipilimumab. Ongoing trials are evaluating novel tyrosine kinase inhibitor and immunotherapy combination regimens, with an emphasis on the promising MET-inhibitor cabozantinib and pembrolizumab plus lenvatinib

Analysis of Aroma Characteristics of Fermented Lingyun Baihao Tea Based on Odor Activity Value

This study aimed to analyze the difference in aroma components and aroma characteristics of different types (white, oolong, yellow and black) of fermented Lingyun Baihao tea. The aroma components were identified by solid phase microextraction (SPME) combined with gas chromatography-mass spectrometry (GC-MS), and odor activity value (OAV) was used to determine the key flavor components. By combined use of principal component analysis (PCA), orthogonal partial least square-discriminant analysis (OPLS-DA), cluster analysis and sensory evaluation, the aroma of fermented Lingyun baihao tea was comprehensively evaluated. The results showed that a total of 48 aroma compounds were identified in the tea samples, including 15 key flavor components and flavor-modifying components (OAV > 0.1). The cumulative interpretation rate R2X (cum) and the cumulative prediction rate Q2 (cum) of the PCA model were 0.984 and 0.846, respectively, and those of the OPLS-DA model were greater than 0.7 and 0.9, respectively. Both models had good fitness. The major differential components were linalool, isoamyl alcohol, 2-methylbutyraldehyde, β-ionone, nonanal and jasmone. The 15 aroma components were classified into three categories by hierarchical cluster analysis (HCA). Class I contained indole and dehydroalinalool, Class II contained linalool, nonanal, phenylacetaldehyde, hexanal, 2-methylbutyraldehyde, isovaleraldehyde, phenylethanol and isobutyraldehyde, and Class III contained jasmone, β-ionone, methyl salicylate, 2-pentylfuran and dimethyl sulfide. Class I was prominent in oolong tea samples, Class II was prominent in black tea samples, Class III was prominent in white tea samples, and Class II and III were prominent in yellow tea samples. These aroma characteristics were consistent with the results of sensory aroma evaluation. GC-MS analysis and OAV calculation combined with PCA, OPLS-DA and HCA can enable the identification and evaluation of Lingyun Baihao fermented tea aroma. The results of this study can provide a reference for the further development of Lingyun Baihao tea

Salvage lenvatinib/everolimus combination therapy after immune checkpoint inhibitor and VEGFR tyrosine kinase inhibitor for metastatic renal cell carcinoma

BackgroundThe optimal treatment for metastatic renal cell carcinoma (mRCC) patients who have progressed after both immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) remains uncertain. Lenvatinib and everolimus (LE) are frequently used in combination as salvage therapy because of their different antitumor mechanisms, but efficacy and toxicity data in this setting are lacking.MethodsWe retrospectively reviewed charts from two academic centers for 71 adult mRCC patients who received LE after prior ICI and TKI exposure. We evaluated patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details. Outcomes of interest included objective response rate (ORR), time to treatment failure (TTF), overall survival (OS), ≥grade 3 toxicities, and schedule or dosage changes, which were evaluated using descriptive statistics, chi-square test, Cox proportional hazards model, and the Kaplan–Meier method.ResultsThe median age was 64 (range 31–84). Most patients had clear cell histology (84.5%) and had undergone nephrectomy (80.3%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). The average ORR was 26.8%, while the median TTF was 5.5 months (95% confidence interval [CI], 3.5–7.6) and the median OS was 9 months (95% CI, 7.6–12.9). Intermediate and poor IMDC risks were independently associated with a significantly worse TTF compared to favorable risk (hazard ratio (HR), 3.03, 95% CI, 1.18–7.79), as was ≥4L treatment vs. 2L/3L treatment (HR, 2.02, 95% CI, 1.08–3.8). Of the 71 patients, 57.7% had ≥grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance.ConclusionsLE therapy is feasible but has modest efficacies following ICI/TKI treatment. Patients with favorable risk or treated earlier may have a better treatment response. These observations need to be confirmed in prospective studies

Corrosion Resistance of Concrete Reinforced by Zinc Phosphate Pretreated Steel Fiber in the Presence of Chloride Ions

This paper aims to provide new insight into a method to improve the chloride ion corrosion resistance of steel fiber reinforced concrete. The steel fiber was pretreated by zinc phosphate before the preparation of the fiber reinforced concrete. Interfacial bond strength, micro-hardness and micro-morphology properties were respectively analyzed in the steel fiber reinforced concrete before and after the chloride corrosion cycle test. The results show that the chloride ion corrosion resistance of the steel fiber was enhanced by zinc phosphate treatment. Compared to plain steel fiber reinforced concrete under chloride ion corrosion, the interfacial bond strength of the concrete prepared by steel fiber with phosphating treatment increased by 15.4%. The thickness of the interface layer between the pretreated steel fiber and cement matrix was reduced by 50%. The micro-hardness of the weakest point in the interface area increased by 54.2%. The micro-morphology of the interface area was almost unchanged before and after the corrosion. The steel fiber reinforced concrete modified by zinc phosphate can not only maintain the stability of the microstructure when corroded by chloride ion but also presents good bearing capacity

Emerging Immunotherapy Approaches for Treating Prostate Cancer

Immunotherapy has emerged as an important approach for cancer treatment, but its clinical efficacy has been limited in prostate cancer compared to other malignancies. This review summarizes key immunotherapy strategies under evaluation for prostate cancer, including immune checkpoint inhibitors, bispecific T cell-engaging antibodies, chimeric antigen receptor (CAR) T cells, therapeutic vaccines, and cytokines. For each modality, the rationale stemming from preclinical studies is discussed along with outcomes from completed clinical trials and strategies to improve clinical efficacy that are being tested in ongoing clinical trials. Imperative endeavors include biomarker discovery for patient selection, deciphering resistance mechanisms, refining cellular therapies such as CAR T cells, and early-stage intervention were reviewed. These ongoing efforts instill optimism that immunotherapy may eventually deliver significant clinical benefits and expand treatment options for patients with advanced prostate cancer

Data from: Recharge and groundwater use in the North China Plain for six irrigated crops for an eleven year period

These data include measured precipitation, measured pan evaporation, planting and harvest dates and measured soil moisture contents of 0-180 cm soil profile at approximately 10-day intervals, annual groundwater table data from 2003 to 2013 by China Agricultural University in cooperation with Luancheng Agro-Ecosystem Experimental Station of Chinese Academy of Sciences.(Related journal paper prepared in cooperation with Cornell University, BEE Soil and Water Lab. Paper abstract follows.) Water tables are dropping by approximately one meter annually throughout the North China Plain mainly due to water withdrawals for irrigating winter wheat year after year. In order to examine whether the drawdown can be reduced we calculate the net water use for an 11 year field experiments from 2003 to 2013 where six irrigated crops (winter wheat, summer maize, cotton, peanuts, sweet potato, ryegrass) were grown in different crop rotations in the North China Plain. As part of this experiment moisture contents were measured each at 20 cm intervals in the top 1.8 m. Recharge and net water use were calculated based on these moisture measurement. Results showed that winter wheat and ryegrass had the least recharge with an average of 27mm/year and 39 mm/year, respectively; cotton had the most recharge with an average of 211 mm/year) followed by peanuts with 118 mm/year, sweet potato with 76 mm/year, and summer maize with 44 mm/year. Recharge depended on the amount of irrigation water pumped from the aquifer and therefore a poor indicators of future groundwater decline. Instead net water use (recharge minus irrigation) was found to be good indicator for the decline of the water table. The smallest amount of net (ground water) used was cotton with an average of 14 mm/year, followed by peanut with 32 mm/year, summer maize with 71 mm/year, sweet potato with 74 mm/year. Winter wheat and ryegrass had the greatest net water use with the average of 198 mm/year and 111 mm/year, respectively. Our calculations showed that any single crop would use less water than the prevalent winter maize summer wheat rotation. This growing one crop instead of two will reduce the decline of groundwater and in some rain rich years increase the ground water level, but will result in less income for the farmers.China Agricultural University Funding:the National Key Technology R&D Program of the People's Republic of China (2011BAD16B15 and 2012BAD14B03), the China Scholarship Council for Xiaolin Yang (Grant No. 201306350107) and the Chinese Universities Scientific Fund (2013YJ001

An insight into the thermal properties of struvite-k by Rietveld refinement method

This work investigated the thermal properties of struvite-k (a main binding phase and a strength-giving mineral from the magnesium potassium phosphate cements) exposed to different conditions by Rietveld Refinement Method coupled with X-ray diffraction analysis (XRD) identification, thermogravimetry/differential scanning calorimetry (TG/DSC) and Fourier-transform infrared spectroscopy (FTIR) method. The struvite-k presented significant vulnerability when exposed to above 70 °C, and destabilized to MgKPO4⋅H2O instead of MgKPO4, where, the remaining (0 3 1) and (2 1 2) planes were attributed to magnesium potassium phosphate monohydrate (MgKPO4·H2O). Coordinate a and c of the struvite-k crystal demonstrated significant responses to the heating temperature in comparison with coordinate b. Increasing the temperature up to 90 °C could decrease the length c of the struvite-k from 11.1022 Å to 9.8493 Å, and decrease its crystal size from 119.9 nm to 6.7 nm. The present work could provide fundamental knowledge on practical applications of MKPCs, such as construction, nuclear waste management, and phosphate recovery

Hydration Performance of Magnesium Potassium Phosphate Cement Using Sodium Alginate as a Candidate Retarder

Retarders are important factors controlling the hydration and properties of magnesium potassium phosphate cements (MKPCs). Boric acid and borax are the most commonly used retarders for MKPC which could control the setting time in a wide range upon changing their content. However, with the increase in borax content, the early strength of MKPC can be reduced, and boron compounds are now included in the EU candidate list of substances of very high concern for authorization, due to their reproductive toxicity. Exploring alternative set retarders to boron compounds is, thus, of significance. This work investigated the effects of a candidate retarder, namely, sodium alginate, on the setting time, mechanical properties, hydration products, and microstructures of MKPC. Sodium alginate presented dramatically retarding effects on MKPCs in the range of 0% to 2% (by mass of water). One percent of sodium alginate by mass of water could extend the setting time of MKPCs from 15 min to 35 min, which presented a better retarding effect than borax (a typical retarder for MKPCs) and produced higher early strength of MKPCs. Adding no more than 1% of sodium alginate did not have a notably adverse effect on the formation of hydration product over the long term, but an unfavorable effect could be found regardless of the sodium alginate content, which could reduce the compressive strength of MKPCs

The Mechanosensitive Ion Channel Piezo Inhibits Axon Regeneration

Neurons exhibit a limited ability of repair. Given that mechanical forces affect neuronal outgrowth, it is important to investigate whether mechanosensitive ion channels may regulate axon regeneration. Here, we show that DmPiezo, a Ca(2+)-permeable non-selective cation channel, functions as an intrinsic inhibitor for axon regeneration in Drosophila. DmPiezo activation during axon regeneration induces local Ca(2+) transients at the growth cone, leading to activation of nitric oxide synthase and the downstream cGMP kinase Foraging or PKG to restrict axon regrowth. Loss of DmPiezo enhances axon regeneration of sensory neurons in the peripheral and CNS. Conditional knockout of its mammalian homolog Piezo1 in vivo accelerates regeneration, while its pharmacological activation in vitro modestly reduces regeneration, suggesting the role of Piezo in inhibiting regeneration may be evolutionarily conserved. These findings provide a precedent for the involvement of mechanosensitive channels in axon regeneration and add a potential target for modulating nervous system repair