[Comparison of the efficacy of different surgical strategies in the treatment of patients with initially resectable gastric cancer liver metastases].

Objective: To examine the impact of varied surgical treatment strategies on the prognosis of patients with initial resectable gastric cancer liver metastases (IR-GCLM). Methods: This is a retrospective cohort study. Employing a retrospective cohort design, the study selected clinicopathological data from the national multi-center retrospective cohort study database, focusing on 282 patients with IR-GCLM who underwent surgical intervention between January 2010 and December 2019. There were 231 males and 51 males, aging (M(IQR)) 61 (14) years (range: 27 to 80 years). These patients were stratified into radical and palliative treatment groups based on treatment decisions. Survival curves were generated using the Kaplan-Meier method and distinctions in survival rates were assessed using the Log-rank test. The Cox risk regression model evaluated HR for various factors, controlling for confounders through multivariate analysis to comprehensively evaluate the influence of surgery on the prognosis of IR-GCLM patients. A restricted cubic spline Cox proportional hazard model assessed and delineated intricate associations between measured variables and prognosis. At the same time, the X-tile served as an auxiliary tool to identify critical thresholds in the survival analysis for IR-GCLM patients. Subgroup analysis was then conducted to identify potential beneficiary populations in different surgical treatments. Results: (1) The radical group comprised 118 patients, all undergoing R0 resection or local physical therapy of primary and metastatic lesions. The palliative group comprised 164 patients, with 52 cases undergoing palliative resections for gastric primary tumors and liver metastases, 56 cases undergoing radical resections for gastric primary tumors only, 45 cases undergoing palliative resections for gastric primary tumors, and 11 cases receiving palliative treatments for liver metastases. A statistically significant distinction was observed between the groups regarding the site and the number of liver metastases (both P<0.05). (2) The median overall survival (OS) of the 282 patients was 22.7 months (95%CI: 17.8 to 27.6 months), with 1-year and 3-year OS rates were 65.4% and 35.6%, respectively. The 1-year OS rates for patients in the radical surgical group and palliative surgical group were 68.3% and 63.1%, while the corresponding 3-year OS rates were 42.2% and 29.9%, respectively. A comparison of OS between the two groups showed no statistically significant difference (P=0.254). Further analysis indicated that patients undergoing palliative gastric cancer resection alone had a significantly worse prognosis compared to other surgical options (HR=1.98, 95%CI: 1.21 to 3.24, P=0.006). (3) The size of the primary gastric tumor significantly influenced the patients' prognosis (HR=2.01, 95%CI: 1.45 to 2.79, P<0.01), with HR showing a progressively increasing trend as tumor size increased. (4) Subgroup analysis indicates that radical treatment may be more effective compared to palliative treatment in the following specific cases: well/moderately differentiated tumors (HR=2.84, 95%CI 1.49 to 5.41, P=0.001), and patients with liver metastases located in the left lobe of the liver (HR=2.06, 95%CI 1.19 to 3.57, P=0.010). Conclusions: In patients with IR-GCLM, radical surgery did not produce a significant improvement in the overall prognosis compared to palliative surgery. However, within specific patient subgroups (well/moderately differentiated tumors, and patients with liver metastases located in the left lobe of the liver), radical treatment can significantly improve prognosis compared to palliative approaches.

Patterns of recurrence and outcomes in patients with luminal breast cancer: a retrospective study.

BACKGROUND: Patients with luminal breast cancer have better prognosis and survival rates compared to patients with non-luminal breast cancers, such as basal-like and HER-2 subtypes, owing to the added benefits of adjuvant endocrine therapy. However, local relapses and distant metastasis still frequently occur. In recent years, more studies on breast cancer relapse and metastasis have focused on non-luminal breast cancers despite there being more number of cases of luminal breast cancer. MATERIALS AND METHODS: In this study, the authors included 387 breast cancer patients with recurrence and metastasis who were treated in their hospital between January 2001 and June 2011, and divided them into luminal and non-luminal groups. The differences in clinical and pathological characteristics, survival rates, and prognostic features after follow-up treatment were retrospectively analyzed in the two groups. RESULTS: The authors found there was a higher proportion of local recurrence and single bone metastasis in luminal group than in the non-luminal group. The risk of recurrence and metastasis in the luminal group two to five years and after five years post-operation continued to be stable, but the risk in the non-luminal group significantly decreased after two years. CONCLUSIONS: Luminal breast cancer patients with recurrence or/and metastasis had better prognosis after reasonable treatment. These results are of potential clinical relevance, especially for clinical prognosis monitoring and targeted therapy interventions in patients with luminal breast cancer.

[The surgical treatment of ovarian cancer metastasis between liver and diaphragm: a report of 83 cases].

Objective: To explore the safety and feasibility of associating diaphragm resection and liver-diaphragmatic metastasis lesions resection for patients with advanced ovarian cancer. Methods: Retrospectively analysis 83 cases(98 times) of advanced ovarian cancer with liver-diaphragmatic metastasis between January 2012 and December 2016 at Department of Liver Surgery, Peking Union Medical College Hospital.The patients were aged from 19 to 75 years.Surgical procedure included metastatic lesions resection(43 times) and stripping(55 times). Operation status, post-operative complications, pathology results and follow-up of the patients were analyzed. Results: Fifteen patients received twice surgical treatment and 68 patients received one time surgical treatment. Postoperative hemorrhage in chest and between liver and diaphragm was not occurred in all cases.Dyspnea and low oxygen saturation were occurred in two cases of stripping patients and 1 case of metastatic lesions resection patients.Results of CT examination indicated that there was medium to large amount of ascites in right chests.The symptoms were relieved after placing thoracic closed drainage.Other patients were recovered smoothly.All patients were diagnosed as ovarian cancer by pathological examination. Conclusion: Associating diaphragm resection is safe and feasible for liver-diaphragmatic metastasis lesions from ovarian cancer.

Plumbagin shows anti-cancer activity in human breast cancer cells by the upregulation of p53 and p21 and suppression of G1 cell cycle regulators.

PURPOSE: Plumbagin, a naphthoquinone constituent of Plumbago zeylanica L. (Plumbaginaceae), is known to exhibit proapoptotic, antiangiogenic and antimetastatic effects in cancer cells. However, the effect of Plumbagin on breast cancer cells and the underlying molecular mechanism has not yet been elucidated. MATERIALS AND METHODS: MCF-7 (a human breast cancer cell line) was exposed different concentrations of Plumbagin (PG), and the anti-proliferative activity was evaluated by the MTT assay. The mechanism of action for the growth inhibitory activity of Plumbagin on MCF-7 cancer cells was evaluated using flow cytometry for cell cycle distribution, and western blot for assessment of expression of potential target proteins. RESULTS: Plumbagin exhibited a significant anti-proliferative activity against human breast cancer cells. Flow cytometric analysis revealed that Plumbagin caused cell cycle arrest at G1 phase. The cell cycle arrest was well correlated with the inhibition of cyclin D1, cyclin E, and upregulation of tumor suppressor protein p53. It further inhibited the expression of anti-apoptotic Bcl-2 family members such as Bcl-xL and Bcl-2, and activated pro-apoptotic proteins like Bax and Bak. CONCLUSION: These findings suggest that the anti-proliferative effect of Plumbagin is due to upregulation of p53 and p21 and suppression of G1 cell cycle regulators.

Effects of AFP gene silencing on Survivin mRNA expression inhibition in HepG2 cells.

We investigated the effects of alpha-fetoprotein (AFP) gene silencing on Survivin expression in HepG2 cells. Small interfering RNA technology was used to downregulate AFP expression in HepG2 cells. An enzyme-linked immunosorbent assay was used to measure AFP concentration in the supernatant before and after transfection. An MTT assay was used to detect cell proliferation activity before and after transfection. We performed flow cytometric analysis to detect the cell apoptosis rate, and reverse transcription-polymerase chain reaction to detect Survivin mRNA levels before and after transfection. Forty-eight hours after transfection, AFP concentration in the supernatant of the experimental group significantly decreased, hepatocellular carcinoma cell growth was inhibited by 43.1%, and the apoptosis rate increased by 24.3%. Survivin mRNA expression was reduced by 78.0% in HepG2 cells. These indicators in the control group and in the blank group did not change significantly. Silencing of AFP expression in HepG2 cells can effectively inhibit the growth of hepatoma cells and promote apoptosis, which may be useful for reducing intracellular Survivin mRNA levels.

Crystal structure of the extracellular segment of integrin alpha Vbeta3.

Integrins are alphabeta heterodimeric receptors that mediate divalent cation-dependent cell-cell and cell-matrix adhesion through tightly regulated interactions with ligands. We have solved the crystal structure of the extracellular portion of integrin alphaVbeta3 at 3.1 A resolution. Its 12 domains assemble into an ovoid "head" and two "tails." In the crystal, alphaVbeta3 is severely bent at a defined region in its tails, reflecting an unusual flexibility that may be linked to integrin regulation. The main inter-subunit interface lies within the head, between a seven-bladed beta-propeller from alphaV and an A domain from beta3, and bears a striking resemblance to the Galpha/Gbeta interface in G proteins. A metal ion-dependent adhesion site (MIDAS) in the betaA domain is positioned to participate in a ligand-binding interface formed of loops from the propeller and betaA domains. MIDAS lies adjacent to a calcium-binding site with a potential regulatory function.

Enhanced antitumor efficacy of resveratrol-loaded nanocapsules in colon cancer cells: physicochemical and biological characterization.

OBJECTIVE: The aim of present work was to prepare resveratrol-loaded lipid-core-nanocapsule (RSV-LNC) and to characterize its ability to target the colon cancer cells. MATERIALS AND METHODS: The lipid-core nanocapsule was prepared by precipitation method. The nanoparticle was prepared and evaluated regarding physical, chemical and biological parameters. RESULTS: The average size of optimized nanocapsule was ~159 nm with a uniform size distribution index of 0.15 (PDI). The RSV-LNC showed a controlled and sustained release pattern with maximum release up to ~70% by the end of 48h study period. LNC showed an excellent cellular uptake potential. LNC showed a typical endocytosis-mediated cellular internalization process and located in the cell cytoplasm. DISCUSSION: Importantly, RSV encapsulated in a nanocapsule showed a superior anticancer effect in HT29 cancer cells than compared to that of free RSV. Consistently, RSV-LNC showed a remarkable ~36% of cell apoptosis indicating its superior anticancer effect. CONCLUSIONS: Based on the in vitro studies, RSV encapsulated in a nanocapsule showed promising potential to increase the therapeutic efficacy in colon cancer cells; however, further studies on animal models are warranted to confirm the improved effects of RSV nanoformulations.

[Effect of intravenous injection of intravenous injection of chlorine on blood oxygen saturation in patients with nasal endoscopic surgery].

Objective:To observe the effect of intravenous injection of chlorine on postoperative analgesia and blood oxygen saturation in patients with nasal endoscopic surgery.Method:According to the standard of American Society of anesthesiologists(ASA) grading assessment for Ⅰ-Ⅱ, undergoing nasal endoscopic surgery of 120 patients were randomly divided into two groups, 60 cases in each group. Control group dezocine 0.8 g/kg+ physiological saline to 100 ml; on the basis of the experimental group with flurbiprofen 2 mg/kg+ physiological saline to 100 ml. Respectively in the postoperative recovery and postoperative 2, 4, 12, 24 and 48 h recording vital signs, pain scores(visual analogue score, VAS) and sedation score(Ramsay score) and observe the adverse reaction rate and patient surveys on the satisfaction of postoperative analgesia.Result:The two groups compared test of TKA group after 4, 8, 12, 24, 36 h, 48 h, 72 h resting VAS score and postoperative 24 h, 48 h, 72 h activities of VAS score were lower than the control group, the difference is statistically significant (F=1 873.26, P< 0.05). After 2 h, 6 h, 2 groups of pH, PaO2, PaCO2, SpO2 compared statistically significant (P> 0.05). After 24h, 48h after test group, PaO2, PaCO2, SpO2 is better than that of the control group(P< 0.05); after 6 h, 24 h, 48 h after the test group patients Ramsay Sedation score than the control group, the difference is statistically significant(F=1 031.35, P< 0.05). The experimental group after TKA patients of pain control education satisfaction and to control or reduce pain method of satisfaction were superior to the control group, the difference significant (χ²=11.02, P< 0.05;χ²=9.33, P< 0.05).Conclusion:The application of intravenous injection of intravenous injection of chlorine in the postoperative pain of nasal endoscopic surgery can significantly improve the analgesic effect, improve the blood gas analysis, improve the analgesic effect, it is worthy of popularization and application.

Crystallization and preliminary crystallographic study of beta-momorcharin.

Beta-Momorcharin from seeds of Momordica charantia, Cucurbitaceae Linn, has been crystallized using a vapor diffusion method. The crystals belong to space group P1 with unit cell parameters: a = 49.09 A, b = 50.58 A, c = 61.12 A, alpha = 72.98 degrees, beta = 78.39 degrees, gamma = 76.97 degrees. There are two molecules in the unit cell and the diffraction data up to 2.4 A resolution were collected on an X-200B area detector, giving an Rmerge of 7.8%.

Protein structural plasticity exemplified by insertion and deletion mutants in T4 lysozyme.

To further investigate the ways in which proteins respond to changes in the length of the polypeptide chain, a series of 32 insertions and five deletions were made within nine different alpha-helices of T4 lysozyme. In most cases, the inserted amino acid was a single alanine, although in some instances up to four residues, not necessarily alanine, were used. Different insertions destabilized the protein by different amounts, ranging from approximately 1 to 6 kcal/mol. In one case, no protein could be obtained. An "extension" mutant in which the carboxy terminus of the molecule was extended by four alanines increased stability by 0.3 kcal/mol. For the deletions, the loss in stability ranged from approximately 3 to 5 kcal/mol. The structures of six insertion mutants, as well as one deletion mutant and the extension mutant, were determined, three in crystal forms nonisomorphous with wild type. In all cases, including previously described insertion mutants within a single alpha-helix, there appears to be a strong tendency to preserve the helix by translocating residues so that the effects of the insertion are propagated into a bend or loop at one end or the other of the helix. In three mutants, even the hydrophobic core was disrupted so as to permit the preservation of the alpha-helix containing the insertion. Translocation (or "register shift") was also observed for the deletion mutant, in this case a loop at the end of the helix being shortened. In general, when translocation occurs, the reduction in stability is only moderate, averaging 2.5 kcal/mol. Only in the most extreme cases does "bulging" or "looping-out" occur within the body of an alpha-helix, in which case the destabilization is substantial, averaging 4.9 kcal/mol. Looping-out can occur for insertions close to the end of a helix, in which case the destabilization is less severe, averaging 2.6 kcal/mol. Mutant A73-[AAA] as well as mutants R119-[A] and V131-[A], include shifts in the backbone of 3-6 A, extending over 20 residues or more. As a result, residues 114-142, which form a "cap" on the carboxy-terminal domain, undergo substantial reorganizations such that the interface between this "cap" and the rest of the protein is altered substantially. In the case of mutant A73-[AAA], two nearby alpha-helices, which form a bend of approximately 105 degrees in the wild-type structure, reorganize in the mutant structure to form a single, essentially straight helix. These structural responses to mutation demonstrate the plasticity of protein structures and illustrate ways in which their three-dimensional structures might changes during evolution.

Integrins, cations and ligands: making the connection.

Integrins are cell adhesion receptors that couple extracellular divalent cation-dependent recognition events with intracellular mechanical and biochemical responses and vice versa, thus affecting every function of nucleated cells. The structural basis of this bidirectional signaling and its dependency on cations has been the focus of intensive study over the past three decades. Significant progress made recently in elucidating the three-dimensional structure of the extracellular and cytoplasmic segments of integrins is giving valuable new insights into the tertiary and quaternary changes that underlie activation, ligand recognition and signaling by these receptors.

Comparative corrosion performance of black oxide, sandblasted, and fine-drawn nitinol wires in potentiodynamic and potentiostatic tests: effects of chemical etching and electropolishing.

The corrosion performance of sandblasted (SB) and smooth fine-drawn (FD) medical-use nitinol wires was compared with the performance of wires with black oxide (BO) formed in air during their manufacture. Potentiodynamic and ASTM F746 potentiostatic tests in a 0.9 % NaCl solution were conducted on wires in their as-received, chemically etched, aged in boiling water, and electropolished states. As-received wires with various surface finishes revealed breakdown potentials in the range from -100 mV to +500 mV; similar passive current density, 10(-6) A/cm(2); and a wide hysteresis on the reverse scan, demonstrating strong susceptibility to localized corrosion. Chemically etched wires with original black oxide displayed consistent corrosion performance and surpassed, in corrosion resistance, electropolished wires that showed significantly lower breakdown (400-700 mV) and localized corrosion potentials ( approximately -50 to +113 mV). Sandblasted and fine-drawn wires exhibited rather inconsistent corrosion behavior. In potentiodynamic tests these wires could perform with equal probability either on the level of pretreated BO wires or rather similar to as-received wires. Both SB and FD wires revealed low breakdown potentials in the PS regime. SEM analysis performed before tests indicated that sandblasting was not efficient for the complete removal of the original scaling, and fine drawing aggravated the situation, resulting in a persistent scaling that contributed to the inferior corrosion performance. Inclusions (oxides, carbides, and oxidized carbides) inherited from the bulk and retained on electropolished surfaces are the cause of their inferior performance compared to chemically etched surfaces. In electropolished wires corrosion was initiated around inclusions.

Recombinant integrin CD11b A-domain blocks polymorphonuclear cells recruitment and protects against skeletal muscle inflammatory injury in the rat.

The beta2 integrin CD11b/CD18 (CR3) is a major adhesion receptor of neutrophils, normally utilized to fend off infections. This receptor contributes, however, to multiple forms of non-infectious inflammatory injury when dysregulated as shown in gene knock-outs and through the use of blocking monoclonal antibodies. The major ligand recognition site of CR3 has been mapped to the A-domain in the CD11b subunit (CD11bA). The recombinant form of this domain exhibits a ligand binding profile similar to that of the holoreceptor. To assess the potential anti-inflammatory activity of CD11bA as a competitive antagonist of CR3 in vivo, we assessed its effects on a developed animal model of traumatic skeletal muscle injury in the rat. Recombinant soluble rat CD11bA-domain fused to glutathione-S-transferase (GST) was administered intravenously in a single dose at 1 mg/kg to nine groups of Wistar rats, five in each group, 30 min before inducing traumatic skeletal muscle injury. Control animals received either a function-blocking anti-CD11b/CD18 monoclonal antibody (1 mg/kg), non-functional mutant forms of the CD11bA (D140GS/AGA, T209/A, D242/A), recombinant GST or buffer alone. In control animals, the wounded muscle showed oedema, erythrocyte extravasation and myonecrosis both within and outside the immediate wounded area (5-10 mm zone) and influx of neutrophils was detected 30 min post-wound, followed by a second wave 3 hr later. Wild-type CD11bA- or anti-CD11b monoclonal antibody (mAb)-treated rats showed a comparable and significant decrease in the number of infiltrating PMN (78 + 4%, n = 70 and 86 +/- 2%, n = 50, respectively) and preservation of the muscular fibres outside the immediate zone of necrosis (75 + 4%, n = 70, 84 +/- 1%, n = 50, respectively), compared to controls. These data demonstrate that CD11bA can be an effective tissue-preserving agent in acute inflammatory muscular injury.

Integrin structure, allostery, and bidirectional signaling.

Alphabeta heterodimeric integrins mediate dynamic adhesive cell-cell and cell-extracellular matrix (ECM) interactions in metazoa that are critical in growth and development, hemostasis, and host defense. A central feature of these receptors is their capacity to change rapidly and reversibly their adhesive functions by modulating their ligand-binding affinity. This is normally achieved through interactions of the short cytoplasmic integrin tails with intracellular proteins, which trigger restructuring of the ligand-binding site through long-range conformational changes in the ectodomain. Ligand binding in turn elicits conformational changes that are transmitted back to the cell to regulate diverse responses. The publication of the integrin alphaVbeta3 crystal structure has provided the context for interpreting decades-old biochemical studies. Newer NMR, crystallographic, and EM data, reviewed here, are providing a better picture of the dynamic integrin structure and the allosteric changes that guide its diverse functions.

Crystal structure of trichosanthin-NADPH complex at 1.7 A resolution reveals active-site architecture.

We describe here the crystal structure of the trichosanthin-NADPH complex determined at a resolution of 1.7 A. The adenine base stacks between Tyr 70 and Tyr 111. Arg 163, Glu 160 and Tyr 70 form hydrogen bonds to N(3), O(3') and, through a water molecule, to N(9) of adenosine, respectively. This is the first high resolution structure of a complex between a ribosome-inactivating protein and a substrate analogue, in which the electron density of the N-glycosidic bond is well defined and the preassociated water, thought to be responsible for hydrolyzing the N-C bond, is also explicitly elucidated.

Identification of a stable complex of trichosanthin with nicotinamide adenine dinucleotide phosphate.

Trichosanthin, a type I ribosome-inactivating protein with RNA N-glycosidase activity, forms a stable complex with nicotinamide adenine dinucleotide phosphate, a substrate analog. Difference UV spectroscopy, fluorescence spectroscopy, and 31P NMR are used to identify the formation of the complex, followed by a crystal structure analysis carried out to elucidate the active-site structure of trichosanthin. The determination of germinal vesicle breakdown indicates that the complex does not, at least for abortion-inducing activity, result in competitive inhibition to the protein.

An isoleucine-based allosteric switch controls affinity and shape shifting in integrin CD11b A-domain.

In response to cell activation signals, integrins switch from a low to a high affinity state. Physiologic ligands bind to integrins through a von Willebrand Factor A-type domain. Crystallographic studies revealed two conformations of this domain, "closed" and "open." The latter crystallizes in complex with a pseudoligand or ligand, suggesting that it represents the high affinity state; data linking structure and activity are lacking however. In this communication, we expressed stable low and high affinity forms of integrin CD11b A-domain and determined their binding isotherms and crystal structures. The low affinity form, generated by deleting an N-terminal extension extrinsic to the domain, did not bind to physiologic ligands, and crystallized in the closed conformation. The high affinity form was generated by either deleting or substituting an invariable C-terminal Ile(316), wedged into a hydrophobic socket in the closed form, but displaced from it in the open structure. Both mutants crystallized in the open conformation, and the Ile(316) --> Gly-modified integrin displayed high affinity. Structural differences between the low and high affinity forms were detected in solution. These data establish the structure-function correlates for the CD11b A-domain, and define a ligand-independent isoleucine-based allosteric switch intrinsic to this domain that controls its conformation and affinity.

Three-dimensional structure of beta-momorcharin at 2.55 A resolution.

Beta-Momorcharin (Mr approximately 29 kDa) is a single-chained ribosome-inactivating protein (RIP) with a branched hexasaccharide bound to Asn51. The crystal structure of beta-momorcharin has been determined using the molecular-replacement method and refined to 2. 55 A resolution. The final structural model gave an R factor of 17. 2% and root-mean-square deviations of 0.016 A and 1.76 degrees from ideal bond lengths and bond angles, respectively. beta-Momorcharin contains nine alpha-helices, two 310 helices and three beta-sheets, and its overall structure is similar to those of other single-chained RIPs. Residues Tyr70, Tyr109, Glu158 and Arg161 are expected to define the active site of beta-momorcharin as an rRNA N-glycosidase. The oligosaccharide is linked to the protein through an N-glycosidic bond, beta-GlcNAc-(1-N)-Asn51, and stretches from the surface of the N-terminal domain far from the active site, which suggests that it should not play a role in enzymatic function. The oligosaccharide of each beta-momorcharin molecule interacts with the protein through hydrogen bonds, although in the crystals most of these are intermolecular interactions with the protein atoms in an adjacent unit cell. This is the first example of an RIP structure which provides information about the three-dimensional structure and binding site of the oligosaccharide in the active chains of RIPs.

Cloning and characterization of a mammalian lithium-sensitive bisphosphate 3'-nucleotidase inhibited by inositol 1,4-bisphosphate.

Discovery of a structurally conserved metal-dependent lithium-inhibited phosphomonoesterase protein family has identified several potential cellular targets of lithium as used to treat manic depression. Here we describe identification of a novel family member using a "computer cloning" strategy. Human and murine cDNA clones encoded proteins sharing 92% identity and were highly expressed in kidney. Native and recombinant protein harbored intrinsic magnesium-dependent bisphosphate nucleotidase activity (BPntase), which removed the 3'-phosphate from 3'-5' bisphosphate nucleosides and 3'-phosphoadenosine 5'-phosphosulfate with Km and Vmax values of 0.5 microM and 40 micromol/min/mg. Lithium uncompetitively inhibited activity with a Ki of 157 microM. Interestingly, BPntase was competitively inhibited by inositol 1,4-bisphosphate with a Ki of 15 microM. Expression of mammalian BPntase complemented defects in hal2/met22 mutant yeast. These data suggest that BPntase's physiologic role in nucleotide metabolism may be regulated by inositol signaling pathways. The presence of high levels of BPntase in the kidney are provocative in light of the roles of bisphosphorylated nucleotides in regulating salt tolerance, sulfur assimilation, detoxification, and lithium toxicity. We propose that inhibition of human BPntase may account for lithium-induced nephrotoxicity, which may be overcome by supplementation of current therapeutic regimes with inhibitors of nucleotide biosynthesis, such as methionine.