The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dube syndrome is required for murine B-cell development

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models. Here, we describe mice deficient in the newly characterized folliculin-interacting protein 1 (Fnip1). In contrast to Flcn, Fnip1(-/-) mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is entirely independent of mTOR activity. We show that this developmental arrest results from rapid caspase-induced pre-B cell death, and that a Bcl2 transgene reconstitutes mature B-cell populations, respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. Our studies thus demonstrate that the FLCN-FNIP complex deregulated in BHD syndrome is absolutely required for B-cell differentiation, and that it functions through both mTOR-dependent and independent pathways.     

Postmorbid learning of saxophone playing in a patient with frontotemporal dementia

Some patients with frontotemporal dementia (FTD) show an artistic enhancement of musical abilities. However, no patients with FTD, to date, have been reported to be able to learn how to play a musical instrument after disease onset. Herein we describe a patient (J. K.) who had never played any musical instruments premorbidly, but who learned to play the saxophone after being diagnosed with a behavioral variant of FTD. He mastered a repertoire that consisted of 10 pieces of Korean folk songs over a period of three years. Furthermore, his saxophone skills were high enough to outperform other students in his class.     

The “ABO Cross-transplantation Problem” in Liver Transplantation in Korea

ABO blood group matching policy between donor and recipients is a chief element of organ allocation. However, O blood group donors may donate to all other blood group recipients, and ABO cross-transplantation has led to excessively long delays for blood group O. To investigate the consequence of this problem, we analyzed the recipients/donor rates according to ABO blood groups and cross-transplantation rates among them. Data about deceased donors and liver transplants performed in Korea from January 2008 to September 2012 were reviewed. The proportion of recipient to donor in the O blood group was lower compared to non-O groups (0.61). The percentage of O blood group transplantations in the Korean Network for Organ Sharing (KONOS) status 2B was lower than non-O groups (13.6%). In the status 1 and 2A groups, 44.4% of O blood group donors were allocated to non-O transplantations. Also, 30.7% O blood group donors were allocated to non-O transplantations in the status 2B groups. In conclusion, the ABO cross-transplantation in blood group O donors has led to lower transplantation rates of blood group O in status 1, 2A, and especially, the 2B group. Therefore, the KONOS allocation system should be re-evaluated to address this problem.     

Does Procurement Technique Affect Posttransplant Graft Function in Deceased Donor Liver Transplantation?

Introduction

Various techniques have been described deceased donor liver transplantation (DDLT) procurement. One is a technique whereby almost total dissection is done in the porta hepatis and perihepatic detachment is carried out before cross-clamping the donor aorta. In another approach, after the donor aorta is cross-clamped, rapid and minimal en bloc dissection is performed with minimal manipulation. We evaluated early posttransplant graft function among liver procurement techniques.

Method

Between January 2008 and August 2012, we performed 45 consecutive adult DDLTs. One patient was excluded from this analysis due to early death from sepsis after transplantation. The 44 included patients were divided into two cohorts according to the procurement technique: A warm dissection (n = 23; 52%) and a cold dissection group (n = 21; 48%). We compared early posttransplant graft function using the aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-bil), and prothrombin time (PT) values of the two groups from the first to seventh postoperative day.

Result

The AST values in the warm group were significantly greater than those in the cold group on postoperative days 3 and 5. In addition, the ALT values in the warm group were greater than those in the cold group on postoperative days 4, 5, and 6. Moreover, the T-bil values in the warm group were greater than those in the cold group on postoperative days 2, 3, 4, 5, 6, and 7. However, there were no differences in PT values.

Conclusion

During liver procurement for DDLT, rapid en bloc procurement with minimal manipulation after clamping the donor aorta achieved better early graft function posttransplantation.     

Reverse shape selectivity of hexane isomer in ligand inserted MOF-74

Separation of linear, mono-branched, and di-branched isomers is critically important in the petrochemical industry. In this computational study, we demonstrate that the ligand inserted Mg-MOF-74 structure leads to a reverse selectivity effect (i.e. phenomenon that preferentially allows larger species molecules to permeate in a gas mixture) of hexane isomers in the resulting material. Molecular dynamics simulations suggest that strong confinement of the di-branched hydrocarbons in the small pores lead to reverse selectivity. Over a magnitude difference in diffusivity between linear alkanes and their di-branched isomers was observed, clearly showing the steric effects imposed by the pore structure.

The ligand inserted Mg-MOF-74 structure leads to a reverse selectivity effect (i.e. phenomenon that preferentially allows larger species molecules to permeate in a gas mixture) of hexane isomers in the resulting material.

In the petrochemical industry, separation of the hexane isomers is an important process that removes impurities for fuel purification and the isolation of mixtures for applied further reaction.^1,2 The sieving of n-hexane and its branched isomers is particularly interesting research because of the varying octane numbers in the isomers affecting the gasoline production,^3–5 and as such, it is imperative to facilitate separation of these isomers. Unfortunately, this separation is particularly challenging due to the similar polarizabilities and chemical inertness of the molecules, leading one to resort to highly energy expensive distillation processes.^1,6The presently used methods such as molecular sieving using zeolites and the conventional distillation processes still include mixtures of the isomers that lowers the overall octane number^7,8 compared to the pure di-branched molecule composition. To discover the adsorbent materials that can completely separate the isomers into their individual components, many researchers have investigated adsorbent materials with an appropriate pore size and shape.^9–12 Recently, metal–organic frameworks (MOFs) have attracted great deal of attention from the researchers due to their potential applications in gas separations,^13–20 CO₂ capture,^21,22 catalysis,^23–26 water harvesting^27–29 and several other applications.^30–32 MOFs are crystalline microporous materials composed of inorganic metal nodes and organic linkers^33–35 and via combining various metal clusters and organic linkers, MOFs can be tuned specifically to ideal shapes and pore chemical environment for targeted gas separations.^36–38 This tunability allows one to potentially design MOFs that are ideal for hexane isomers. Bárcia et al.³⁹ firstly used MOFs called Zn(BDC)(DABCO)_0.5 (MOF-1) to separate hexane isomers, although this MOF showed low adsorption capacities. Also, Herm et al.¹² synthesized a MOF named Fe₂(BDP)₃ (BDP²⁻ = 1,4-benzenedipyrazolate), which contain triangular pore channels that can discriminate hexane isomers better than the commercial standard. More recently, Lv et al.⁴⁰ demonstrated that [Fe₃(μ3-O)(COO)₆] and 2,2-bis(4-carboxyphenyl)-hexafluoropropane (6FDCA) have strong capability to separate n-hexane from its branched isomers on the basis of a kinetically controlled molecular sieve separation.Overall, conventional wisdom dictates that one would seek to design materials whose pore limiting diameter can separate the molecules of interest within the mixture. With that being said, there have been few observances where the ordering based on kinetic diameters is reversed (in what is called reverse selectivity).⁴¹ Previous study by Bárcia et al.⁴² used the concept of “length entropy” to describe the adsorption and separation behavior in UiO-66(Zr). They showed that UiO-66(Zr) preferentially adsorb branched alkanes over their linear isomer, in what they called “reverse selectivity”. Moreover, Pan et al.⁴³ described the unusual reverse selective separation of n-butane from normal hydrocarbons above C₄ in a fluorinated MOF with 1D channels. Additionally, reverse selectivity has also been mentioned in recent works with IRMOF-8 (ref. 44) and UiO-66@SiO₂ (ref. 45) with regards to linear and iso-alkane separation.In our previous computational work, we designed the ligand inserted MOF frameworks using the ligand insertion strategy. Using computational analysis, these structures showed increase in the working capacity of CO₂ under humid flue gas conditions,²² utility as a catalyst for enhanced ethane oxidation²⁵ and potential usage in water harvesting material.²⁹ In the current work, the dpt ligand inserted Mg-MOF-74 structures with 1-D channel was used to examine the reverse selectivity of hexane isomer and separation properties by considering mixtures of n-hexane and its branched isomers (2,2-dimethylbutane, 2,3-dimethylbutane, 2-methylpentane and 3-methylpentane). In the context of the hexane isomer separation, the inserted ligand finely tuned the shape and the size of the pores within the MOF such that branched isomer can reverse selectively pass through the MOF channel.Optimization of the MOFs and the hexane isomer binding energy calculations were conducted using the first-principles calculations through the density functional theory (DFT) as implemented by the plane-wave pseudopotential approach in Quantum Espresso.⁴⁶ The second version of a van der Waals dispersion-corrected density functional (vdW-DF2)⁴⁷ was used to describe the dispersion interactions. Ultrasoft pseudopotentials were used for GGA and vdW-DF2 calculations. A 2 × 2 × 2 k-point mesh was used for the Brillouin zone sampling in the reciprocal space. The kinetic energy and charge density planewave cutoff were set to 30 Ry and 240 Ry, respectively.All molecular dynamics simulations were carried out using the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) program.⁴⁸ In the simulations, the MOF structures are set to be fixed with the dpt ligand and the hexane isomers considered to be flexible, incorporating all intramolecular motions such as bond vibrations, bond angle bending, and torsional motions. All non-bonded interactions between the atoms were calculated using the Lennard-Jones (LJ) potential. Adsorbate–adsorbate and adsorbate–MOF interactions were truncated at 14 Å and at 12.8 Å with analytical tail-corrections applied for interactions beyond this cutoff distance, respectively. The LJ parameters for the atoms of the MOF were taken from the UFF⁴⁹ and The TraPPE force field were employed to model the inter- and intramolecular interactions of the hexane isomers as previous studies reported that these models accurately model the adsorption and diffusion properties of alkanes⁵⁰ and nHEX⁵¹ in the MOFs. Initially, all systems were equilibrated for 2 ns in an NVT ensemble, and afterwards, another 10 ns of simulation was performed in the NVT ensemble during which the equilibrated phase space trajectories were stored at every 10 ps. These trajectories were then used to analyze the diffusion behavior of the hexane isomers with the diffusion coefficients calculated from the mean square displacements (MSD) of the molecules using the Einstein''s relation.The ligand insertion strategy within the MOF-74 structure can be used to reconfigure the pore space to enhance the separation performance. To demonstrate this, a size-matching regulated ligand (2,4-di(4-pyridinyl)-1,3,5-triazine (dpt)) was inserted as shown in Fig. 1(a).Open in a separate windowFig. 1Illustration of pore space partitioned Mg-MOF-74 using ligands 2,4-di(4-pyridinyl)-1,3,5-triazine. (a) Viewed along z axis and (b) side view of the channels showing the cylindrical channel.The insertion of 2,4-di(4-pyridinyl)-1,3,5-triazine (dpt) ligands into the hexagonal channels of Mg-MOF-74 was demonstrated in our previous theoretical study on catalyst for ethane oxidation.²⁵ In the previous work, the computed DFT binding energy of the dpt ligand was −198.3 kJ mol⁻¹ in the Mg-MOF-74 structures, providing evidence that the ligands would stay intact and not wash away, post synthesis. The dpt ligands were inserted such that the distance between the two dpt ligands is 8.3 Å along the channel direction in the z-axis (Fig. 1(b)). In the alkane separations, configurational and length entropy effects may act in a completely different manner. These effects plays a bigger role for separating linear and branched alkanes in materials such as AFI⁵² and MOF-74 that have cylindrical channels. Hence, it is important to consider both the maximum diameter (i.e. molecular length)⁵³ of the molecules as well as kinetic diameter. As can be seen from 53,54

Oncologic Outcomes after Adjuvant Chemotherapy Using FOLFOX in MSI-H Sporadic Stage III Colon Cancer

Background

Little is known of the oncological outcomes after adjuvant FOLFOX chemotherapy in patients with stage III colon cancer showing microsatellite instability high (MSI-H). In the present study we investigated the prognostic impact of MSI-H in patients with stage III colon cancer receiving FOLFOX chemotherapy.

Methods

We analyzed the MSI status in 127 patients with stage III colon cancer who underwent curative surgical resection followed by FOLFOX chemotherapy between January 2003 and December 2010. We assessed disease-free and overall survival (OS) in patients with MSI-H colon cancer compared with those showing microsatellite instability low or microsatellite stable (MSI-L/MSS) disease.

Results

Sixteen of the patients (12.6 %) were MSI-H, and 111 patients (87.4 %) were MSI-L/MSS. There was no significant difference between patients showing MSI-H and MSI-L/MSS except for age (P = 0.030), tumor location (P < 0.001), and differentiation (P = 0.031). Compared with MSI-L/MSS colon cancer, patients with MSI-H colon cancer had no significant difference in 5-year disease-free and OS (72.2 vs 68.5 %, P = 0.874; 68.1 vs 71.1 %, P = 0.437).

Conclusions

Our study indicates that FOLFOX chemotherapy can be considered to treat stage III colon cancer patients with MSI-H after surgery, although the study was not randomized and included only a limited number of patients.