Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers.

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

Paeoniflorin loaded liposomes modified with glycyrrhetinic acid for liver-targeting: preparation, characterization, and pharmacokinetic study.

OBJECTIVE: To enhance the retention times and therapeutic efficacy of paeoniflorin (PF), a liver-targeted drug delivery system has been developed using glycyrrhetinic acid (GA) as a ligand. SIGNIFICANCE: The development and optimization of GA-modified PF liposomes (GPLs) have shown promising potential for targeted delivery to the liver, opening up new possibilities for liver disease treatment. METHODS: This study aimed to identify the best prescriptions using single-factor experiments and response surface methodology. The formulation morphology was determined using transmission electron microscopy. Tissue distribution was observed through in vivo imaging, and pharmacokinetic studies were conducted. RESULTS: The results indicated that GPLs, prepared using the thin film dispersion method and response surface optimization, exhibited well-dispersed and uniformly sized particles. The in vitro release rate of GPLs was slower compared to PF monomers, suggesting a sustained release effect. The liver-targeting ability of GA resulted in stronger fluorescence signals in the liver for targeted liposomes compared to non-targeted liposomes. Furthermore, pharmacokinetic studies demonstrated that GPLs significantly prolonged the residence time of PF in the bloodstream, thereby contributing to prolonged efficacy. CONCLUSION: These findings suggest that GPLs are more effective than PF monomers in terms of controlling drug release and delivering drugs to specific targets, highlighting the potential of PF as a liver-protective drug.

Single-cell atlas of epithelial and stromal cell heterogeneity by lobe and strain in the mouse prostate.

BACKGROUND: Evaluating the complex interplay of cell types in the tissue microenvironment is critical to understanding the origin and progression of diseases in the prostate and potential opportunities for intervention. Mouse models are an essential tool to investigate the molecular and cell-type-specific contributions of prostate disease at an organismal level. While there are well-documented differences in the extent, timing, and nature of disease development in various genetically engineered and exposure-based mouse models in different mouse strains and prostate lobes within each mouse strain, the underlying molecular phenotypic differences in cell types across mouse strains and prostate lobes are incompletely understood. METHODS: In this study, we used single-cell RNA-sequencing (scRNA-seq) methods to assess the single-cell transcriptomes of 6-month-old mouse prostates from two commonly used mouse strains, friend virus B/NIH jackson (FVB/NJ) (N = 2) and C57BL/6J (N = 3). For each mouse, the lobes of the prostate were dissected (anterior, dorsal, lateral, and ventral), and individual scRNA-seq libraries were generated. In situ and pathological analyses were used to explore the spatial and anatomical distributions of novel cell types and molecular markers defining these cell types. RESULTS: Data dimensionality reduction and clustering analysis of scRNA-seq data revealed that basal and luminal cells possessed strain-specific transcriptomic differences, with luminal cells also displaying marked lobe-specific differences. Gene set enrichment analysis comparing luminal cells by strain showed enrichment of proto-Oncogene targets in FVB/NJ mice. Additionally, three rare populations of epithelial cells clustered independently of strain and lobe: one population of luminal cells expressing Foxi1 and components of the vacuolar ATPase proton pump (Atp6v0d2 and Atp6v1g3), another population expressing Psca and other stem cell-associated genes (Ly6a/Sca-1, Tacstd2/Trop-2), and a neuroendocrine population expressing Chga, Chgb, and Syp. In contrast, stromal cell clusters, including fibroblasts, smooth muscle cells, endothelial cells, pericytes, and immune cell types, were conserved across strain and lobe, clustering largely by cell type and not by strain or lobe. One notable exception to this was the identification of two distinct fibroblast populations that we term subglandular fibroblasts and interstitial fibroblasts based on their strikingly distinct spatial distribution in the mouse prostate. CONCLUSIONS: Altogether, these data provide a practical reference of the transcriptional profiles of mouse prostate from two commonly used mouse strains and across all four prostate lobes.

Controlling the emission frequency of graphene nanoribbon emitters based on spatially excited topological boundary states.

Graphene nanoribbons (GNRs) with atomically precise heterojunction interfaces are exploited as nanoscale light emitting devices with modulable emission frequencies. By connecting GNRs with different widths and lengths, topological boundary states can be formed and manipulated. Using first-principles-based atomistic simulations, we studied the luminescence properties of a STM GNR junction and explored the applications of these topological states as nanoscale light sources. Taking advantage of the ultrahigh resolution of the STM tip, direct injection of high energy carriers at selected boundary states can be achieved. In this way, the emission color can be controlled by precisely changing the tip position. The GNR heterojunction can therefore represent a robust and controllable light-emitting device that takes a step forward towards the fabrication of nanoscale graphene-based optoelectronic devices.

Predicting distribution of Zanthoxylum bungeanum Maxim. in China.

BACKGROUND: With the growth of economic benefits brought by Zanthoxylum bungeanum Maxim. and the increasing market demand, this species has been widely introduced and cultivated in China. It is important to scientifically select suitable areas for artificial planting and promotion, and to understand the status and potential of Z. bungeanum resources. RESULTS: The maximum entropy (MaxEnt) model and ArcGIS technologies were used to analyze the climatic suitability of Z. bungeanum based on known distribution data, combined with environmental data in China. Z. bungeanum was mainly distributed in subtropical and mid-eastern warm temperate regions. The total suitable area (high and medium suitability) accounted for 32% of China's total land area, with high suitability areas composing larger percentage, reaching 1.93 × 106 km2. The suitable range (and optimum value) of the key environmental variables affecting the distribution of Z. bungeanum were the maximum temperature in February of 2.8-17.7 °C (10.4 °C), the maximum temperature in March of 8.6-21.4 °C (16.3 °C), the maximum temperature in December of 2.5-17.1 °C (9.9 °C), the maximum temperature in November of 7.7-22.2 °C (14.5 °C) and the mean temperature in March of 3.2-16.2 °C (12.0 °C). CONCLUSIONS: The model developed by MaxEnt was applicable to explore the environmental suitability of Z. bungeanum.

Theoretical investigation of real-time charge dynamics in open systems coupled to bulk materials.

Environmental effects play an important role on the electron dynamics of open systems, which provide channels for dissipation of electrons and energy in the systems. However, accurate description of the environment of quantum systems is still challenging. The environment is usually assumed to be a quasi-one-dimensional reservoir in previous theoretical studies. In this work, we focus on systems that are adsorbed on bulk surfaces. Two different approaches to describe the spectral details of the environment are adopted and compared: the Lorentzian decomposition approach and the complex absorbing potential (CAP) approach. To achieve similar accuracy for the spectral density of the environment, it is shown that the Lorentzian decomposition approach is computationally more efficient than the CAP approach, especially for bulk systems. The electron dynamics is then followed using the nonequilibrium Green's function method for two systems: a modeling bulk surface system and a scanning tunneling microscope junction. Dissipation paths of excited charge carriers can be analyzed, which provide insights into the understanding of excitation dynamics in bulk materials.

Time-dependent density functional theory for open systems with a positivity-preserving decomposition scheme for environment spectral functions.

Understanding electronic dynamics on material surfaces is fundamentally important for applications including nanoelectronics, inhomogeneous catalysis, and photovoltaics. Practical approaches based on time-dependent density functional theory for open systems have been developed to characterize the dissipative dynamics of electrons in bulk materials. The accuracy and reliability of such approaches depend critically on how the electronic structure and memory effects of surrounding material environment are accounted for. In this work, we develop a novel squared-Lorentzian decomposition scheme, which preserves the positive semi-definiteness of the environment spectral matrix. The resulting electronic dynamics is guaranteed to be both accurate and convergent even in the long-time limit. The long-time stability of electronic dynamics simulation is thus greatly improved within the current decomposition scheme. The validity and usefulness of our new approach are exemplified via two prototypical model systems: quasi-one-dimensional atomic chains and two-dimensional bilayer graphene.

Improving the efficiency of hierarchical equations of motion approach and application to coherent dynamics in Aharonov-Bohm interferometers.

Several recent advancements for the hierarchical equations of motion (HEOM) approach are reported. First, we propose an a priori estimate for the optimal number of basis functions for the reservoir memory decomposition. Second, we make use of the sparsity of auxiliary density operators (ADOs) and propose two ansatzs to screen out all the intrinsic zero ADO elements. Third, we propose a new truncation scheme by utilizing the time derivatives of higher-tier ADOs. These novel techniques greatly reduce the memory cost of the HEOM approach, and thus enhance its efficiency and applicability. The improved HEOM approach is applied to simulate the coherent dynamics of Aharonov-Bohm double quantum dot interferometers. Quantitatively accurate dynamics is obtained for both noninteracting and interacting quantum dots. The crucial role of the quantum phase for the magnitude of quantum coherence and quantum entanglement is revealed.

Renal telocytes contribute to the repair of ischemically injured renal tubules.

Telocytes (TCs), a distinct type of interstitial cells, have been identified in many organs via electron microscopy. However, their precise function in organ regeneration remains unknown. This study investigated the paracrine effect of renal TCs on renal tubular epithelial cells (TECs) in vitro, the regenerative function of renal TCs in renal tubules after ischaemia-reperfusion injury (IRI) in vivo and the possible mechanisms involved. In a renal IRI model, transplantation of renal TCs was found to decrease serum creatinine and blood urea nitrogen (BUN) levels, while renal fibroblasts exerted no such effect. The results of histological injury assessments and the expression levels of cleaved caspase-3 were consistent with a change in kidney function. Our data suggest that the protective effect of TCs against IRI occurs via inflammation-independent mechanisms in vivo. Furthermore, we found that renal TCs could not directly promote the proliferation and anti-apoptosis properties of TECs in vitro. TCs did not display any advantage in paracrine growth factor secretion in vitro compared with renal fibroblasts. These data indicate that renal TCs protect against renal IRI via an inflammation-independent pathway and that growth factors play a significant role in this mechanism. Renal TCs may protect TECs in certain microenvironments while interacting with other cells.

[Bone marrow mesenchymal stem cell-derived exosome protects kidney against ischemia reperfusion injury in rats].

OBJECTIVE: To explore the protective effects and mechanism of exosomes derived from bone marrow mesenchymal stem cells (BM-MSC) on ischemia reperfusion injury (IRI) in rats. METHODS: Rat-MSC were isolated, cultured and identified.Exosome was extracted from BM-MSC and observed under transmission electron microscope (TEM). The expression of surface molecular marker CD63 was tested by flow cytometry. Male Sprague-Dawley rats were randomly grouped into sham-operated (Sham), ischemia reperfusion (IR), MSC-treated (IR+MSC), MSC-derived exosome-treated (IR+MSC-ex) and fibroblast-derived exosome-treated (IR+F-ex) groups. The model for ischemia reperfusion injury was constructed. The serum levels of creatinine and blood urea nitrogen (BUN) were tested in each group. The histomorphological changes in of renal tissue samples were examined by hematoxylin and eosin-stained tissue samples. Cellular apoptosis was examined by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) staining. The expression levels of proinflammatory cytokines interleukin 1ß and tumor necrosis factor α were examined by reverse transcription (RT)-PCR. And the expression level of caspase-3 was examined by Western blot. RESULTS: Rat BM-MSCs were successfully isolated and cultured. Dectection of surface markers revealed high expression levels of CD29 and CD44 and a low expression level of CD34. MSC differentiated successfully into osteoblasts and lipocytes after growing in osteoblast- and lipocyte-inducing media respectively. Typical appearances of exosome were observed under transmission electron microscope. CD63 was positive on flow cytometry. Compared with the IR group, the IR+MSC and IR+MSC-ex groups showed low levels of serum creatinine and BUN, mild pathological injury, decreased number of apoptotic cells and low expression of inflammatory factors and caspase-3 (IR group, 4 310 ± 616;IR+MSC group, 2 569 ± 530; IR+MSC-ex group, 3 144 ± 343, both P < 0.05). CONCLUSION: Rat BM-MSC-derived exosome protects against ischemia reperfusion injury with decreased inflammatory response and apoptosis in rats.

Meta-analytic and MaxEnt model prediction, the distribution of the Bactrocera minax (Diptera: Tephritidae), in China under changing climate.

The Tephritidae family causes damage to fruits in tropical and subtropical regions around the world, with Bactrocera minax Enderlein (Diptera: Tephritidae) widely distributed in China, causing severe economic damage to Chinese citrus. Currently, preventing the rapid spread of B. minax remains an effective strategy to control it as the climate continues to warm in the future. In this context, it is crucial to understand the potential geographic range of B. minax under climate change. We used meta-analysis to assess the survival of Tephritidae insects under temperature stress. We also used the maximum entropy (MaxEnt) model to predict the suitable regions and migration trajectories of B. minax in China under current and future climatic conditions. Through comprehensive analysis of the experimental data, we found that the survival rate of Tephritidae insects in the suitable temperature range showed an increasing trend with the increase in warming extent. Using the MaxEnt model, we observed that the highly suitable area, as well as the moderately suitable area of B. minax, were expanding in all 3 future climate scenarios, with the distribution moving toward the high latitude region and the coastal region of China. Our results also indicate that temperature and precipitation contribute more to the model in the current year. Combining multiexperiment data, our study demonstrates that the potential distribution of B. minax in China will expand under future climate warming scenarios, and these predictions will provide important information for monitoring B. minax and informing managers in developing control strategies.

Preparation of paeoniflorin-glycyrrhizic acid complex transethosome gel and its preventive and therapeutic effects on melasma.

Paeoniflorin (PF) and glycyrrhizic acid (GL) have skin beautifying effects of anti-inflammation, anti-oxidation, inhibition of melanin formation, and reduction of skin pigmentation. To improve the transdermal permeability of PF and GL in transdermal drug delivery system (TDDS) and enhance their anti-melasma efficacy, PF-GL transethosome (PF-GL-TE) was prepared by ethanol injection method, and finally gelled with carbomer-940 to form PF-GL-TE gel. Consequently, the obtained PF-GL-TE is small and uniform, with an average particle size and a PDI value of about 167.9 nm and 0.102. PF-GL-TE gel showed sustained release behavior and high transdermal permeability in vitro release and transdermal tests. Meanwhile, PF-GL-TE gel played significant preventive effects on melasma induced by progesterone injection and ultraviolet radiation B (UVB) irradiation. According to the results of H&E staining and Masson staining of rat skin, PF-GL-TE gel can alleviate the skin inflammation of and reduce the loss of collagen fibers of back skin in the melasma model rats. Compared with the PF-GL mixture gel, PF-GL-TE gel significantly attenuated the oxidative damage of liver and skin by increasing the activity of SOD and reducing the content of MDA. The results of Western blot showed that PF-GL-TE gel might down-regulate melanin-related proteins expressions of MITF/TYR/TRP1 and TRP2 to prevent and treat melasma. These findings indicate that PF-GL-TE gel is an effective TDDS for delivering PF and GL into the skin, providing a promising preparation for effective prevention and treatment of melasma.

Geographical distribution of two major quarantine fruit flies (Bactrocera minax Enderlein and Bactrocera dorsalis Hendel) in Sichuan Basin based on four SDMs.

Both Bactrocera minax and Bactrocera dorsalis are phytophagous insects, and their larvae are latent feeders, which cause great damage and economic losses to agriculture production and trade. This study aimed to provide a scientific reference for researching and developing the feasible countermeasures against these two pests. Based on the distribution data of B. minax and B. dorsalis in China, obtained from the Chinese herbaria, investigation and literature. Four niche models (Garp, Bioclim, Domain, and Maxent) were used to analyze the key environmental factors affecting the distribution of both pests and to build prediction models of the potential distribution in Sichuan Basin. Combined with two statistical standards, area under the receiver operating characteristic curve (AUC) and Kappa, the validity of prediction models were analyzed and compared. The results show that: the average AUC values of the four models are all above 0.90, and the average Kappa values are all above 0.75, indicating that the four models are suitable for predicting the potential distribution area of B. minax and B. dorsalis. The annual range of temperature, the mean temperature in the driest quarter, the mean temperature in the warmest quarter, the annual precipitation, and the precipitation in driest month are the key environmental factors affecting the distribution of B. minax, while the mean diurnal temperature range, the mean temperature in the driest quarter, the seasonal temperature variations and the precipitation in driest month affect the potential distribution of B. dorsalis. The suitable areas for B. minax are mainly concentrated in the eastern of Sichuan Basin, while the suitable areas for B. dorsalis are concentrated in the southeastern. Except for the Bioclim model, the highly-suitable area for both pests predicted by the other three models are all greater than 15.94 × 104 km2 and the moderately-suitable areas are greater than 13.57 × 104 km2. In conclusion, the suitable areas for both pests in Sichuan Basin are quite wide. Therefore, the relevant authorities should be given strengthened monitoring of both pests, especially in areas with high incursion rates.

Potential distribution prediction of Ceracris kiangsu Tsai in China.

Ceracris kiangsu Tsai (C. kiangs) is a kind of forest pest, which can harm nearly 100 kinds of weeds and crops. In this study, based on 314 species distribution points of C. kiangsu which were obtained from Chinese herbaria, literatures and investigation, and data of three future climate scenarios presented by CMIP6, two niche models (Garp, Maxent) were used to predict the suitable area of C. kiangsu in China. The result shows that the main environmental factors affecting the distribution of C. kiangsu are precipitation of driest month (bio14) and min temperature of coldest month (bio6). No matter now and future, the potential distribution areas of C. kiangsu in China are mainly in the south of Qinling-Huaihe River. Under current scenarios, the areas of the total, highly, moderately and poorly suitable of C. kiangsu in China are 160.65 × 104 km2, 31.70 × 104 km2, 60.36 × 104 km2 and 68.59 × 104 km2 respectively. The southern Hubei, western Jiangxi and eastern Hunan are highly-suitable areas. Under SSP1-2.6 and SSP2-4.5 scenarios, both the total suitable area and the highly suitable show a decreasing tread in 2050s. Compared to the 2050s, the total suitable area will coninue to decease in 2090s under SSP1-2.6, while it will increase under SSP2-4.5. The highly suitable area will increase in both scenarios, and the increased percentage under SSP2-4.5 is greater than that under SSP1-2.6. Under SSP5-8.5 scenarios, the total suitable area will increase by 1.83% in the 2050s, and decrease by 1.17% in the 2090s. The highly suitable area in the 2050s and 2090s under this scenarios is larger than under current scenarios. No matter what the scenario, the southern part of Yunnan, the southeast of Sichuan and the southwest of Chongqing will become highly-suitable areas as the climate continues to warm and should be monitored more cosely.

Future habitat changes of Bactrocera minax Enderlein along the Yangtze River Basin using the optimal MaxEnt model.

Background: Bactrocera minax (Enderlein, 1920) (Diptera: Tephritidae) is a destructive citrus pest. It is mainly distributed throughout Shaanxi, Sichuan, Chongqing, Guizhou, Yunnan, Hubei, Hunan, and Guangxi in China and is considered to be a second-class pest that is prohibited from entering that country. Climate change, new farming techniques, and increased international trade has caused the habitable area of this pest to gradually expand. Understanding the suitable habitats of B. minax under future climate scenarios may be crucial to reveal the expansion pattern of the insect and develop corresponding prevention strategies in China. Methods: Using on the current 199 distribution points and 11 environmental variables for B. minax, we chose the optimal MaxEnt model to screen the dominant factors that affect the distribution of B. minax and to predict the potential future distribution of B. minax in China under two shared socio-economic pathways (SSP1-2.6, SSP5-8.5). Results: The current habitat of B. minax is located at 24.1-34.6°N and 101.1-122.9°E, which encompasses the provinces of Guizhou, Sichuan, Hubei, Hunan, Chongqing, and Yunnan (21.64 × 104 km2). Under future climate scenarios, the potential suitable habitat for B. minax may expand significantly toward the lower-middle reaches of the Yangtze River. The land coverage of highly suitable habitats may increase from 21.64 × 104 km2 to 26.35 × 104 × 104 km2 (2050s, SSP5-8.5) ~ 33.51 × 104 km2 (2090s, SSP5-8.5). This expansion area accounts for 29% (2050s, SSP1-2.6) to 34.83% (2090s, SSP1-2.6) of the current habitat. The center of the suitable habitat was predicted to expand towards the northeast, and the scenario with a stronger radiative force corresponded to a more marked movement of the center toward higher latitudes. A jackknife test showed that the dominant variables affecting the distribution of B. minax were the mean temperature of the driest quarter (bio9), the annual precipitation (bio12), the mean diurnal range (bio2), the temperature annual range (bio7), and the altitude (alt). Discussion: Currently, it is possible for B. minax to expand its damaging presence. Regions with appropriate climate conditions and distribution of host plants may become potential habitats for the insects, and local authorities should strengthen their detection and prevention strategies. Climate changes in the future may promote the survival and expansion of B. minax species in China, which is represented by the significant increase of suitable habitats toward regions of high altitudes and latitudes across all directions but with some shrinkage in the east and west sides.

Prediction of the potential suitable habitat of Echinococcus granulosus, the pathogen of echinococcosis, in the Tibetan Plateau under future climate scenarios.

Echinococcosis is a zoonotic parasitic infectious disease caused by human or domestic animals infected with Echinococcus granulosus. China is the country with the heaviest disease burden caused by Echinococcosis in the world. Therefore, it is feasible to evaluate the prevalence and distribution of echinococcosis using relevant ecological methods, combined with environmental factors and human activities. In this study, MaxEnt was used to predict the distribution range of E. granulosus in China under current and future climate scenarios and explain the impact of environmental variables on its distribution. The results showed that elevation (El), annual mean temperature (bio1), human footprint (Hf), annual precipitation (bio12), mean temperature of warmest quarter (bio10), and mean temperature of wettest quarter (bio8) were identified as the dominant environmental variables. In Tibet, the most suitable habitats (25.9 × 104 km2) of E. granulosus were distributed in Nyingchi and Qamdo in the east, Shigatse and Shannan in the south, and Ali in the west. In Sichuan, the most suitable habitat (18.83 × 104 km2) was located in Aba, Ganzi, and Liangshan. In Qinghai, the most suitable habitat (13.05 × 104 km2) mainly included Yushu in the southwest; Guoluo in the southeast; Haidong, Huangnan, Xining, and Hainan in the east; and Haixi in the west. In Gansu, the most suitable habitat (7.36 × 104 km2) was located in Gannan and Linxia in the southwest and Wuwei and Dingxi in the middle. In Yunnan, the most suitable habitat (1.53 × 104 km2) was distributed in Diqing in the northwest. Under future climate scenarios, the area of the most suitable habitat of E. granulosus showed an obvious expansion trend, with an increase of 44.64-70.76%. Trajectory trend of centroids showed that the most suitable habitat would move to the west in the future, and the increased areas were mainly located in the west of the current most suitable habitat. AUC values of the training data and test data were 0.936 ± 0.001 ~ 0.97 ± 0.006 and 0.912 ± 0.006 ~ 0.956 ± 0.015, respectively. The result can provide a theoretical basis for the prevention, monitoring, and early warning of echinococcosis in China.

Suitability changes of Citrus medica L. var. sarcodactylis Swingle, a medicine-food plants affected by climate warming using the optimized MaxEnt model.

Climatic variables are important conditions for plant growth, development and reproduction. Citrus medica L. var. sarcodactylis Swingle (Rutaceae: Citrus) is one of the traditional bulk Chinese medicinal materials in China with the effects of bacteriostasis, anti-inflammatory, anti-oxidation, anti-cancer cells, regulating the immun. Analyzing the impact of climate change on geographical distribution of C. medica L. var. sarcodactylis can provide strong support for its production layout and agricultural zoning. In our paper, MaxEnt and ArcGIS were applied to simulate the suitable areas of C. medica L. var. sarcodactylis in China from the perspectives of bioclimate, soil, topographic factors and human activities, and the future climate scenarios generated by global climate models (GCMs) were selected to predict its suitable areas in 2050s and 2090s. Results showed that, 1) Under current climate condition, areas of the total, most, moderately and poorly suitable habitats of C. medica L. var. sarcodactylis in China were 177.36×104 km2, 22.27×104 km2, 51.96×104 km2 and 103.13×104 km2 respectively. The range of the most suitable habitat was the narrowest, which was located in the middle east of Sichuan, western Chongqing in the upstream of the Yangtze River Basin, southern Guizhou and western Guangxi in the upstream of the Pearl River Basin, central and southern Yunnan and Southeast Tibet in the Middle-Lower reaches of the Southwest River Basin and western Taiwan. 2) Under the future climate change scenarios, the total suitable area showed a significant increase trend in 2090s, and the change of most, moderately and poorly suitable habitats showed no obvious law. 3) Under SSP1-2.6, SSP2-4.5 and SSP5-8.5 scenarios, the centroid of the most suitable habitat of C. medica L. var. sarcodactylis would move to the northwest, southeast and southwest respectively.

MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression.

Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.

CD4 T cell-activating neoantigens enhance personalized cancer vaccine efficacy.

Personalized cancer vaccines aim to activate and expand cytotoxic antitumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4+ T cell activation, we generated a vaccine (PancVAX2) targeting both major histocompatibility complex class I- (MHCI-) and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8+ T cells into the tumor with lower PD-1 expression after reactivation compared with the CD8+ vaccine alone. Vaccine-induced neoantigen-specific Th1 CD4+ T cells in the tumor were associated with decreased Tregs. Consistent with this, PancVAX2 was associated with more proimmune myeloid-derived suppressor cells and M1-like macrophages in the tumor, demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4+ T cell-specific neoantigens for personalized cancer vaccine modalities.