Cross-linked Sodium Hyaluronate Gel with PLLA-b-PEG Microsphere for Facial Contouring in Chinese: A Retrospective Study.

BACKGROUND: In Asia, the demand for cosmetic facial treatments has surged due to technological advancements, increased social acceptability, and affordability. Poly-L-lactic acid (PLLA) fillers, known for their biocompatibility and biodegradability, have emerged as a popular choice for facial contouring, yet studies specifically addressing their use in Asian populations are scarce. METHODS: This retrospective study examined 30 Chinese patients who underwent facial contouring with PLLA fillers, focusing on product composition, injection techniques, and safety measures. A comprehensive clinical evaluation was performed, including the Global Aesthetic Improvement Scale (GAIS) and Global Impression of Change Scale (GICS) for effectiveness and patient satisfaction, respectively. RESULTS: No significant difference in GAIS scores was observed between injectors and blinded evaluators over a 12-month period, indicating consistent effectiveness. Patient satisfaction remained high, with GICS scores reflecting positive outcomes. The safety profile was favorable, with no serious adverse events reported. The study highlighted the importance of anatomical knowledge to avoid complications, particularly in areas prone to blindness. CONCLUSIONS: PLLA fillers offer a safe, effective option for facial contour correction in the Asian population, achieving high patient satisfaction and maintaining results over time. The study underscores the need for tailored approaches in cosmetic procedures for Asians, considering their unique facial structures and aesthetic goals. Further research with larger, multicenter cohorts is recommended to validate these findings and explore long-term effects. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Maitake beta-glucan enhances umbilical cord blood stem cell transplantation in the NOD/SCID mouse.

Beta glucans are cell wall constituents of yeast, fungi and bacteria, as well as mushrooms and barley. Glucans are not expressed on mammalian cells and are recognized as pathogen-associated molecular patterns (PAMPS) by pattern recognition receptors (PRR). Beta glucans have potential activity as biological response modifiers for hematopoiesis and enhancement of bone marrow recovery after injury. We have reported that Maitake beta glucan (MBG) enhanced mouse bone marrow (BMC) and human umbilical cord blood (CB) cell granulocyte-monocyte colony forming unit (GM-CFU) activity in vitro and protected GM-CFU forming stem cells from doxorubicin (DOX) toxicity. The objective of this study was to determine the effects of MBG on expansion of phenotypically distinct subpopulations of progenitor and stem cells in CB from full-term infants cultured ex vivo and on homing and engraftment in vivo in the nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse. MBG promoted a greater expansion of CD34+CD33+CD38- human committed hematopoietic progenitor (HPC) cells compared to the conventional stem cell culture medium (P = 0.002 by ANOVA). CD34+CXCR4+CD38- early, uncommitted human hematopoietic stem cell (HSC) numbers showed a trend towards increase in response to MBG. The fate of CD34+ enriched CB cells after injection into the sublethally irradiated NOS/SCID mouse was evaluated after retrieval of xenografted human CB from marrow and spleen by flow cytometric analysis. Oral administration of MBG to recipient NOS/SCID mice led to enhanced homing at 3 days and engraftment at 6 days in mouse bone marrow (P = 0.002 and P = 0.0005, respectively) compared to control mice. More CD34+ human CB cells were also retrieved from mouse spleen in MBG treated mice at 6 days after transplantation. The studies suggest that MBG promotes hematopoiesis through effects on CD34+ progenitor cell expansion ex vivo and when given to the transplant recipient could enhance CD34+ precursor cell homing and support engraftment.

Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer.

The heat shock protein 90 (Hsp90) has a critical role in malignant transformation. Whereas its ability to maintain the functional conformations of mutant and aberrant oncoproteins is established, a transformation-specific regulation of the antiapoptotic phenotype by Hsp90 is poorly understood. By using selective compounds, we have discovered that small-cell lung carcinoma is a distinctive cellular system in which apoptosis is mainly regulated by Hsp90. Unlike the well-characterized antiapoptotic chaperone Hsp70, Hsp90 is not a general inhibitor of apoptosis, but it assumes this role in systems such as small-cell lung carcinoma, in which apoptosis is uniquely dependent on and effected through the intrinsic pathway, without involvement of caspase elements upstream of mitochondria or alternate pathways that are not apoptosome-channeled. These results provide important evidence for a transformation-specific interplay between chaperones in regulating apoptosis in malignant cells.

Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90.

Hsp90 is a chaperone protein that allows cancer cells to tolerate the many components of dysregulated pathways. Its inactivation may result in targeting multiple molecular alterations and, thus, in reverting the transformed phenotype. The PU-class, a purine-scaffold Hsp90 inhibitor series, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of this class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. The study identifies water soluble derivatives (>5 mM in PBS pH 7.4) of nanomolar potency (IC(50) approximately 50 nM) in cellular and animal models of cancer. Binding affinities of these compounds for Hsp90 correlate well with their biological activities. When administered in vivo to mice bearing MDA-MB-468 human breast cancer xenografted tumors, these agents result in pharmacologically relevant concentrations and, accordingly, in modulation of Hsp90-client proteins in tumors.

BRAF mutation predicts sensitivity to MEK inhibition.

The kinase pathway comprising RAS, RAF, mitogen-activated protein kinase kinase (MEK) and extracellular signal regulated kinase (ERK) is activated in most human tumours, often through gain-of-function mutations of RAS and RAF family members. Using small-molecule inhibitors of MEK and an integrated genetic and pharmacologic analysis, we find that mutation of BRAF is associated with enhanced and selective sensitivity to MEK inhibition when compared to either 'wild-type' cells or cells harbouring a RAS mutation. This MEK dependency was observed in BRAF mutant cells regardless of tissue lineage, and correlated with both downregulation of cyclin D1 protein expression and the induction of G1 arrest. Pharmacological MEK inhibition completely abrogated tumour growth in BRAF mutant xenografts, whereas RAS mutant tumours were only partially inhibited. These data suggest an exquisite dependency on MEK activity in BRAF mutant tumours, and offer a rational therapeutic strategy for this genetically defined tumour subtype.

Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel.

PURPOSE: Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Continuous inhibition of EGFR signaling is thought necessary for optimal inhibition of tumor cell proliferation. We hypothesized that continuous gefitinib may antagonize the effects of cytotoxics that inhibit tumor cells in other phases of the cell cycle. Furthermore, we hypothesized that intermittent dosing would allow for dose escalation and greater inhibition of EGFR-dependent antiapoptotic pathways. EXPERIMENTAL DESIGN: To test these assertions, we compared combinations of paclitaxel and gefitinib using either intermittent or continuous dosing schedules in mice. RESULTS: We found that when used in combination with paclitaxel, pulsatile gefitinib was significantly superior to continuous dosing. When gefitinib was administered for one or two consecutive days before paclitaxel, much higher doses could be given safely. Two days of gefitinib treatment before paclitaxel was most effective, causing significantly greater mean tumor regression and a higher percentage of complete responses than other schedules. CONCLUSIONS: The results suggest that the dose and schedule of an EGFR inhibitor required to effectively inhibit proliferation may differ from that required to stimulate apoptosis or to induce other effects. The former may require continuous EGFR inhibition to maintain cell cycle arrest, whereas sensitization to apoptosis may be optimally induced by profound but temporary inhibition of survival pathways. Our data suggest that the effects of receptor inhibition vary as a function of dose and schedule and that continuous administration of tyrosine kinase inhibitors may not be the best schedule with which to combine such agents with taxanes.

Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics.

Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. We describe here a new human peptide deformylase (Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previously not thought to be necessary in mammalian cells. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. We designed and synthesized 33 chemical analogs of actinonin; all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner; removal of actinonin led to a recovery of the membrane potential consistent with indirect effects on the electron transport chain. In animal models, oral or parenteral actinonin was well tolerated and inhibited human prostate cancer and lung cancer growth. We conclude that HsPDF is a new human mitochondrial enzyme that may provide a novel selective target for anticancer therapy by use of actinonin-based antibiotics.

Microarray analysis of prostate cancer progression to reduced androgen dependence: studies in unique models contrasts early and late molecular events.

Three unique variants of the CWR22 human prostate cancer xenograft model (CWR22LD1, LD2, and LD3) with a decrease in dependence on androgens were selected under noncastrate conditions, i.e., by outgrowth after transplantation into male NCR (AT) nu mice without testosterone supplementation. These variants were unable to grow in castrated male mice. For comparison, a second set of variants with even less dependence on androgens (castrate-resistant) were derived following outgrowth from CWR22 (CWR22Rv1 and RC) or CWRLD1 (CWR22RS) after transplantion in castrated male mice. The androgen receptor (AR) gene in the CWR22LD variants was transcriptionally active and was neither mutated nor significantly overexpressed compared to CWR22. Oligonucleotide microarray analysis showed distinctly different profiles of dysregulated gene expression among the CWR22LD variants. Groups of only 26-41 genes were dysregulated greater than threefold with a different proportion of up versus downregulated genes in each variant. Only one of the castrate-resistant variants (CWR22Rv1) had a highly overexpressed AR gene but AR in this variant and the two other castrate-resistant variants, CWR22 RS and RC, was not mutated beyond that seen in CWR22. In contrast to the CWR22LD variants, a total of 342, 295, and 222 genes were dysregulated at least threefold in CWR22Rv1, CWR22RS, and CWR22RC, respectively, differing as well in the proportion of up versus downregulated genes. Many of the genes dysregulated in CWR22LD1, LD2, and LD3 were further dysregulated in CWR22Rv1, RC, or RS. The most downregulated gene was microseminoprotein beta (MSPB). Along with cyclin D1, the most upregulated gene by an order of magnitude compared to other upregulated genes was hepatocyte growth factor (HGF) (scatter factor). These results suggest that the onset in the loss of androgen dependence in CWR22 proceeds through multiple pathways and does not require any direct change in the status of AR. However, upregulation of other survival pathways like that involving HGF in these studies could co-activate AR signaling. The endogenous overexpression of genes regulating sterol biosynthesis also observed in castrate-resistant CWR22 variants delineated a clinically relevant, compensatory mechanism for overcoming androgen deprivation reaffirming a central role for AR signaling in this process.

Maitake beta-glucan MD-fraction enhances bone marrow colony formation and reduces doxorubicin toxicity in vitro.

Previous studies have indicated that MD-fraction (MDF), in which the active component is beta 1,6-glucan with beta 1,3-branches, has anti-tumor activity as an oral agent and acts as an immune adjuvant. Since some other beta glucans appear to promote mobilization of hematopoietic stem cells, the effects of a beta glucan extract from the Maitake mushroom "MD-fraction" on hematopoietic stem cells were examined in a colony forming assay. Here we report for the first time that MDF has a dose response effect on mouse bone marrow cells (BMC) hematopoiesis in vitro. Using the Colony Forming Unit (CFU) assay to detect formation of granulocyte-macrophage (CFU-GM) colonies, and the XTT cytotoxicitiy assay to measure BMC viability, the data showed that the addition of MDF significantly enhanced the development of CFU-GM in a dose range of 50-100 microg/ml (p<0.004). The mechanism of action included significant increase of nonadherent BMC viability, which was observed at MDF doses of 12.5-100 microg/ml (p<0.005). In the presence of Doxorubicin (DOX), MDF promoted BMC viability and protected CFU-GM from DOX induced toxicity. In addition, MDF treatment promoted the recovery of CFU-GM colony formation after BMC were pretreated with DOX. These studies provided the first evidence that MDF acts directly in a dose dependent manner on hematopoietic BMC and enhances BMC growth and differentiation into colony forming cells.

The cyclin-dependent kinase inhibitor flavopiridol potentiates gamma-irradiation-induced apoptosis in colon and gastric cancer cells.

PURPOSE: Flavopiridol is a cyclin-dependent kinase inhibitor currently under development by the National Cancer Institute both as a single agent and in combination with chemotherapy. There have been numerous reports that flavopiridol potently enhances the induction of apoptosis by chemotherapy. However, the effect of flavopiridol on radiotherapy (RT)-induced apoptosis has been largely untested. RT has become the cornerstone of adjuvant treatment of colorectal and gastric cancer. In view of this, we elected to evaluate the effect of flavopiridol on potentiating RT-induced apoptosis in the human colon cancer cell line HCT-116 and the gastric cancer cell line MKN-74. EXPERIMENTAL DESIGN: The efficacy of combination of gamma-irradiation and flavopiridol was tested in vitro in MKN-74 and HCT-116 cells and correlated to changes in p21 expression. HCT-116 cells were also established as tumors in nude mice and treated with gamma-irradiation and flavopiridol either as single agents or in sequential combinations such that flavopiridol was either given 7 h before, concomitantly, or 3 and 7 h after gamma-irradiation. RESULTS: Flavopiridol significantly enhanced the induction of apoptosis by gamma-irradiation in both cell lines as measured by quantitative fluorescent microscopy, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and cytochrome c release. To achieve the best effect, it was important to expose the tumor cells to gamma-irradiation before the flavopiridol. This sequence dependence was confirmed in vivo. When gamma-irradiation was administered 7 h before flavopiridol, 42% of the tumor-bearing animals were rendered disease free, compared with no animals treated with either gamma-irradiation or flavopiridol alone. Examination of the p21 status of HCT-116 and MKN-74 cells, after treatment with sequential gamma-irradiation and flavopiridol, indicated a loss of p21 protein expression. Loss of p21 was mainly due to cleavage by caspases. HCT-116 cells that lack p21 (p21(-/-)) also exhibited sensitization to gamma-irradiation and showed an even greater enhancement of gamma-irradiation-induced apoptosis by flavopiridol when compared with the parental HCT-116 cells. CONCLUSIONS: These studies indicate that gamma-irradiation followed by flavopiridol enhances apoptosis and yields significantly increased tumor regressions and cures that are not achievable with radiation alone. These results indicate that flavopiridol can potently enhance the effect of gamma-radiation both in vitro and in vivo and may provide a new means to treat patients with locally advanced gastrointestinal cancers.

The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 selectively potentiates radiation response of human tumors in nude mice, with a marked improvement in therapeutic index.

PURPOSE: The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) markedly potentiates the efficacy of many cytotoxic agents against several human cancer xenografts, irrespective of tumor EGFR expression levels. We subsequently investigated the extent to which ZD1839 might improve radiation therapy (RT) in similar animal models of human cancer within the limits of tolerance at a relevant organ site. EXPERIMENTAL DESIGN: We carried out studies of ZD1839 in in vivo models of human non-small cell lung (A549 and SK-LC-16) and breast (MDA-MB468) cancers and human mesothelioma (JMN). The tumors were implanted s.c. over the rib cage or on the most proximate breast and RT given ventral dorsally to the chest only, with mediastinal protection. After the tumor reached a palpable size (0.4-0.6 mm), treatment was initiated with the maximum-tolerated dose (MTD) of ZD1839 (150 mg/kg once daily x 5 for 2 successive weeks), RT (a total of 40 Gy given fractionally at 4 Gy once daily x 5 for 2 successive weeks), or both ZD1839 and RT. RESULTS: This level of RT induced no untoward effects in the mice and was effective (18-72%) in bringing about regression of the tumors with a few complete regressions. ZD1839 alone, given p.o. on the same schedule at its MTD (150 mg/kg), was modestly inhibitory (35-40%) to tumor growth. RT and ZD1839 could be given together at the same doses on the same schedule, resulting in marked regression (50-99%) and a large number of complete regressions of each of the tumors studied. In these studies, the MTD of ZD1839 could be combined with the MTD of RT with no change in schedule or increase toxicity over ZD1839 or RT alone. CONCLUSIONS: ZD1839 significantly enhanced the antitumor action of RT against the test tumors without significant adverse effects, increasing the therapeutic selectively of ionizing radiation in these model systems. These results predict substantial benefits for this multimodality regimen of therapy in patients.

Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression.

PDX (10-propargyl-10-deazaaminopterin) is a novel anti-folate with improved membrane transport and polyglutamylation in tumor cells. In prior studies, PDX exhibited enhanced efficacy over methotrexate (MTX) in lung and breast carcinoma xenografts. Because MTX is active in the treatment of aggressive non-Hodgkin's lymphoma (NHL), we compared the efficacy of PDX and MTX against five lymphoma cell lines: RL (transformed follicular lymphoma), HT, SKI-DLBCL-1 (diffuse large B cell), Raji (Burkitt's), and Hs445 (Hodgkin's disease). After 5-day continuous in vitro exposure, PDX demonstrated > 10-fold greater cytotoxicity than MTX in all cell lines (IC50PDX = 3-5 nM, IC50MTX = 30-50 nM). We then compared the in vivo effects of anti-folates against three established human NHL xenografts in NOD/SCID mice. Tumor bearing animals were treated with saline (control) or the maximum tolerated doses of MTX (40 mg/kg) or PDX (60 mg/kg) via an intraperitoneal route twice weekly for 2 weeks. Almost 90% of HT lymphomas treated with PDX completely regressed, whereas, those treated with MTX treatment had only modest growth delays. In two other xenografts, tumor bearing mice had complete regression rates of 56% (RL) and 30% (SKI-DLBCL-1) after PDX therapy. No regressions and only minor growth inhibition was noted after MTX therapy. RT-PCR analysis for the expression of genes involved in folate metabolism demonstrated that increased sensitivity to PDX correlated with higher RFC-1 gene expression with no difference in FPGS or FPGH levels, suggesting that measurement of tumor RFC-1 gene expression level may be a predictor of response to PDX. These results demonstrate that the PDX has markedly greater potential activity against human NHL than MTX and warrants further preclinical and clinical evaluation.

Flavopiridol enhances the effect of docetaxel in vitro and in vivo in human gastric cancer cells.

Gastric cancer is one of the leading causes of cancer death throughout the world. It is a disease in desperate need of new therapeutic approaches. Docetaxel, a semisynthetic taxane, has shown potent activity against a broad range of solid tumors. However, in gastric cancer, response rates to docetaxel remain only approximately 20%. In these studies we show that flavopiridol, a cyclin-dependent kinase inhibitor, potentiates docetaxel-induced apoptosis 3-fold in MKN-74 human gastric cells. This effect is sequence dependent, such that flavopiridol must follow docetaxel to induce this effect. Docetaxel induces transient arrest in the M phase of the cell cycle. Cells exit mitosis in a specific time window without cytokinesis with a decrease in cyclin B1/cdc-2 kinase activity and MPM-2 labeling. Flavopiridol treatment of docetaxel-treated cells enhances the exit from mitosis with a more rapid decrease in mitotic markers including MPM-2 labeling and cyclin B1/cdc2 kinase activity. In contrast, pretreatment with flavopiridol prevents cells from entering mitosis by inhibiting cyclin B1/cdc-2 kinase activity, thus antagonizing the docetaxel effect. The testing of this combination against MKN-74 xenografts confirms the sequence dependency. Treatment of MKN-74 tumor-bearing xenografts with docetaxel at a dose of 10 mg/kg followed 3-7 h later by flavopiridol at a dose of 2.5 mg/kg resulted in a 1-18% decrease in tumor volume. In contrast, treatment with docetaxel alone at this same dose resulted in a 394% increase in tumor volume. When flavopiridol was given immediately after docetaxel, the effect was not statistically different from that of docetaxel alone. The reverse combination of flavopiridol followed 7 h later by docetaxel was similar to treatment with docetaxel alone. Flavopiridol alone had no effect in this tumor model. Thus, flavopiridol, when combined with docetaxel in a sequence-specific manner, may provide a completely new therapeutic approach in the treatment of gastric cancer.

[Application of Mckissock reduction mammaplasty technique in treatment of giant breast tumor].

OBJECTIVE: To obtain postoperative desirable appearance of the deformed breast we apply Mckissock reduction mammaplasty technique in treatment of giant benign breast tumor. METHODS: According to the principle of Mckissock reduction mammaplasty technique, we design a special incision to remove the tumor in company with the proceeding of mammaplasty. RESULTS: 11 cases of operation with satisfactory results for giant benign tumors have been performed since 1993. CONCLUSIONS: Standard reduction mammaplasty technique has turned out to be an effective remedy for giant tumor spoiling the appearance of the breast.

Drg1, a novel target for modulating sensitivity to CPT-11 in colon cancer cells.

Treatment of the human colon cancer cells Hct116 with SN-38 (an active metabolite of CPT-11) resulted in G2 cell cycle arrest without induction of apoptosis. However, subsequent treatment of SN-38-treated Hct116 cells with flavopiridol induced apoptosis. One of the genes markedly up-regulated during cell cycle arrest by SN-38 and suppressed during apoptosis by SN-38 followed by flavopiridol in Hct116 cells is Drg1. We found that Drg1 had profound effects on SN-38 sensitivity. Inhibition of endogenous Drg1 expression in Hct116 cells by stable expression of an antisense (AS) Drg1 cDNA increased the sensitivity of cells to undergo apoptosis by SN-38. Clonogenic and apoptosis assays with AS Drg1-expressing cells showed a 2-fold decrease in the IC50 and a 4-5-fold increase in induction of apoptosis with SN-38. Conversely, the forced expression of Drg1 in SW620 cells increased the resistance of these cells to SN-38-induced apoptosis by 2-5-fold. Moreover, when xenografted in mice, AS Drg1-expressing Hct116 cells were 3-fold more sensitive to CPT-11 as compared with vector transfected Hct116 cells. Similarly, tumors established from Drg1 overexpressing SW620 cells were more resistant to CPT-11 as compared with tumors established from vector-transfected SW620 cells in mice. Taken together, our data suggest that Drg1 is a novel gene that plays a direct role in resistance to CPT-11. Inhibition of Drg1 may provide a new means to increase the sensitivity of colon cancer cells to CPT-11.

[Improved technique for macrocheilia].

OBJECTIVE: To introduce an improved technique for Macrocheilia. The traditional technique for macrocheilia with direct suture and Z-plasty was improved to decrease postoperative complications, e.g. dynamic abnormality, obvious scar and recurrence due to scar contraction. METHODS: Outside of the new commissure, a triangle flap of the upper lip vermilion was designed, created and inserted to the lower lip. The orbicularis oris muscle was anatomically replaced. Skin Z-plasty was made with triangle flap transferring from the upper to the lower instead. RESULTS: Since August 1985, the new technique has been used in 12 cases of Macrocheilia. All the patients obtained satisfactory results with nice configuration and good function without dynamic abnormality and obvious scar. CONCLUSION: The new technique is a more reasonable method for macrocheilia with nice configuration, good function and fewer complications.