Co-delivery of Plinabulin and Tirapazamine boosts anti-tumor efficacy by simultaneously destroying tumor blood vessels and killing tumor cells.

It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG-b-PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG-b-PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9 % tumor suppression rate and a 20 % cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy.

[Application of three-dimensional ultrasound technique in repairing dorsal foot wounds with medial sural artery perforator flaps].

Objective: To investigate the accuracy of positioning perforator of medial sural artery with three-dimensional ultrasound technique guided by a wide band linear matrix array volume transducer probe before operation, and the effectiveness of the flap design based on this in repairing the dorsal foot wounds. Methods: Between January 2019 and December 2022, 30 patients with skin and soft tissue defects of the dorsal foot were treated. There were 19 males and 11 females, with an average age of 43.9 years (range, 22-63 years). There were 12 cases of traffic accident injury, 15 cases of heavy crushing injury, and 3 cases of machine injury. The time from injury to hospitalization was 1-8 hours (mean, 3.5 hours). The wounds in size of 5 cm×3 cm to 17 cm×5 cm were thorough debrided and covered with vacuum sealing drainage dressing. Then the wounds were repaired with the medial sural artery perforator flaps after no obvious infection observed. To obtain the complete three-dimensional image, the number and position of the medial sural artery perforator branches and the position of the main blood vessels in the muscle were detected and recorded by wide band linear matrix array volume transducer probe before operation. Suitable perforating branches were selected to design the flap and guide the flap incision on this basis. The size of the perforating flap ranged from 6 cm×4 cm to 18 cm×6 cm. The sensitivity and positive predictive value were calculated by comparing preoperative exploration with intraoperative observation of perforating branches, so as to evaluate the positioning accuracy of three-dimensional ultrasound technique. The donor sites were sutured directly in 25 cases and repaired with free skin grafting in 5 cases. Results: The 60 perforating branches of medial sural artery were found before operation and 58 during operation in 30 patients. Among them, pre- and intra-operative perforations were consistent with 56. The sensitivity was 93.3% and positive predictive value was 96.6%. The intramuscular position and route of the main blood vessels were basically consistent with the pre- and intra-operative observation. All flaps survived and wounds healed by first intention. All incisions at the donor sites healed by first intention, and all skin grafts survived. All patients were follow up 9-24 months (mean, 14.7 months). The appearance, color, and texture of the flaps were good, and no obvious effect on wearing shoes and walking. At last follow-up, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hind score ranged from 80 to 92, with an average of 87.5. The patient satisfaction was excellent in 29 cases and good in 1 case. Conclusion: The three-dimensional ultrasound technique guided by the wide band linear matrix array volume transducer probe can accurately locate the perforating branch of the medial sural artery, and the three-dimensional imaging is more intuitive, which can be used to guide the design and incision of the medial sural artery perforator flap.

Correction: Hindering the unlimited proliferation of tumor cells synergizes with destroying tumor blood vessels for effective cancer treatment.

Correction for 'Hindering the unlimited proliferation of tumor cells synergizes with destroying tumor blood vessels for effective cancer treatment' by Ya Liu et al., Biomater. Sci., 2024, 12, 1294-1306, https://doi.org/10.1039/D3BM01858J.

Tumor Microenvironment Remodeling-Mediated Sequential Drug Delivery Potentiates Treatment Efficacy.

Toll-like receptor 7/8 agonists, such as imidazoquinolines (IMDQs), are promising for the de novo priming of antitumor immunity. However, their systemic administration is severely limited due to the off-target toxicity. Here, this work describes a sequential drug delivery strategy. The formulation is composed of two sequential modules: a tumor microenvironment remodeling nanocarrier (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4, termed CA4-NPs) and an immunotherapy nanocarrier (apcitide peptide-decorated poly(l-glutamic acid)-graft-IMDQ-N3 conjugate, termed apcitide-PLG-IMDQ-N3). CA4-NPs, as a vascular disrupting agent, are utilized to remodel the tumor microenvironment for enhancing tumor coagulation and hypoxia. Subsequently, the apcitide-PLG-IMDQ-N3 could identify and target tumor coagulation through the binding of surface apcitide peptide to the GPIIb-IIIa on activated platelets. Afterward, IMDQ is activated selectively through the conversion of "-N3" to "-NH2" in the presence of hypoxia. The biodistribution results confirm their high tumor uptake of activated IMDQ (22.66%ID/g). By augmenting the priming and immunologic memory of tumor-specific CD8+ T cells, 4T1 and CT26 tumors with a size of ≈500 mm3 are eradicated without recurrence in mouse models.

Introducing urea into tirapazamine derivatives to enhance anticancer therapy.

Tirapazamine (TPZ) has been approved for multiple clinical trials relying on its excellent anticancer potential. However, as a typical hypoxia-activated prodrug (HAP), TPZ did not exhibit survival advantages in Phase III clinical trials when used in combination therapy due to the insufficient hypoxia levels in patients' tumors. In this study, to improve the therapeutic effects of TPZ, we first introduced urea to synthesize a series of urea-containing derivatives of TPZ. All urea-containing TPZ derivatives showed increased hypoxic cytotoxicity (9.51-30.85-fold) compared with TPZ, while maintaining hypoxic selectivity. TPZP, one of these derivatives, showed 20-fold higher cytotoxicity than TPZ while maintaining a similar hypoxic cytotoxicity ratio. To highly efficiently deliver TPZP to the tumors and reduce its side effects on healthy tissues, we further prepared TPZP into a nanodrug with fibrin-targeting ability: FT11-TPZP-NPs. CA4-NPs, a vascular disrupting agent, was used to increase the fibrin level within tumors and exacerbate tumor hypoxia. By being combined with CA4-NPs, FT11-TPZP-NPs can accumulate in the hypoxia-aggravated tumors and activate sufficiently to kill tumor cells. After a single-dose treatment, FT11-TPZP-NPs + CA4-NPs showed a high inhibition rate of 98.1% against CT26 tumor models with an initial volume of ∼480 mm3 and four out of six tumors were completely eliminated; it thereby exerted a significant antitumor effect. This study provides a new strategy for improving the therapeutic effect of TPZ and other HAPs in anticancer therapy.

Association between Dietary Inflammatory Index and Bone Mineral Density Changes among Pregnant Women: A Prospective Study in China.

OBJECTIVES: This study aims to examine the relationship between dietary inflammatory index (DII) and bone mineral density (BMD) changes among Chinese pregnant women, offering valuable insights for dietary guidance during pregnancy. METHODS: 289 pregnant women were enrolled in this cohort. Serum inflammatory factors and ultrasonic BMD were measured at the first, second, and the third trimesters. DII scores were calculated based on a semi-quantitative food frequency questionnaire (FFQ) and divided into tertiles. We compared the differences in inflammatory factors in serum across the tertiles of DII and changes in BMD at the second and third trimesters across the tertiles. RESULTS: The participants with higher DII scores had higher total energy intakes than those with lower DII scores. The serum level of interleukin-6 (IL-6) was significantly different across the tertiles of the DII. Women who had lower DII scores had higher T-scores and Z-scores in the BMD assessment. In the test of trends, after adjusting potential covariates, including educational level, physical activity, body mass index, and calcium, vitamin D, or multivitamin supplements, DII values were determined to be positively related to the maternal BMD lost. CONCLUSIONS: DII was positively associated with serum IL-6. Meanwhile, higher DII scores were associated with more bone mass loss in pregnant women. We recommend adhering to a lower-DII diet to preserve BMD during pregnancy.

[A prospective study of super-thin anterolateral thigh flap harvesting assisted by high-frequency color Doppler ultrasound in detecting perforators in deep adipose layers].

Objective: To investigate the clinical application of high-frequency color Doppler ultrasound (HFCDU) in detecting perforators in the deep adipose layers for harvesting super-thin anterolateral thigh flap (ALTF). Methods: Between August 2019 and January 2023, 45 patients (46 sides) with skin and soft tissue defects in the foot and ankle were treated, including 29 males and 16 females, aged from 22 to 62 years, with an average of 46.7 years. The body mass index ranged from 19.6 to 36.2 kg/m 2, with an average of 23.62 kg/m 2. The causes of injury included traffic accident injury in 15 cases, heavy object crush injury in 20 cases, mechanical injury in 8 cases, heat crush injury in 1 case, and chronic infection in 1 case. There were 20 cases on the left side, 24 cases on the right side, and 1 case on both sides. After thorough debridement, the wound size ranged from 5 cm×4 cm to 17 cm×11 cm. All patients underwent free super-thin ALTF transplantation repair. HFCDU was used to detect the location of the perforators piercing the deep and superficial fascia, as well as the direction and branches of the perforators within the deep adipose layers before operation. According to the preoperative HFCDU findings, the dimensions of the super-thin ALTF ranged from 6 cm×4 cm to 18 cm×12 cm. The donor sites of the flaps were directly sutured. Results: A total of 55 perforators were detected by HFCDU before operation, but 1 was not found during operation. During operation, a total of 56 perforators were found, and 2 perforators were not detected by HFCDU. The positive predictive value of HFCDU for identifying perforator vessels was 98.2%, and the sensitivity was 96.4%. Among the 54 perforators accurately located by HFCDU, the orientation of the perforators in the deep adipose layers was confirmed during operation. There were 21 perforators (38.9%) traveled laterally and inferiorly, 12 (22.2%) traveled medially and inferiorly, 14 (25.9%) traveled laterally and superiorly, 5 (9.3%) traveled medially and superiorly, and 2 (3.7%) ran almost vertically to the body surface. Among the 54 perforators accurately located by HFCDU, 35 were identified as type 1 perforators and 12 as type 2 perforators (HFCDU misidentified 7 type 2 perforators as type 1 perforators). The sensitivity of HFCDU in identifying type 1 perforators was 100%, with a positive predictive value of 83.3%. For type 2 perforators, the sensitivity was 63.2%, and the positive predictive value was 100%. The surgeries were successfully completed. The super-thin ALTF had a thickness ranging from 2 to 6 mm, with an average of 3.56 mm. All super-thin ALTF survived, however, 1 flap experienced a venous crisis at 1 day after operation, but it survived after emergency exploration and re-anastomosis of the veins; 1 flap developed venous crisis at 3 days after operation but survived after bleeding with several small incisions; 3 flaps had necrosis at the distal edge of the epidermis, which healed after undergoing dressing changes. All 45 patients were followed up 6-18 months (mean, 13.6 months). Three flaps required secondary defatting procedures, while the rest had the appropriate thickness, and the overall appearance was satisfactory. Conclusion: Preoperative application of HFCDU to detect the perforator in the deep adipose layers can improve the success and safety of the procedure by facilitating the harvest of super-thin ALTF.

Hindering the unlimited proliferation of tumor cells synergizes with destroying tumor blood vessels for effective cancer treatment.

The rational combination of chemotherapy drugs can improve the curative effect of cancer treatment. As two early recognized tumor hallmarks, the limitless replicative potential of tumor cells is essential for the development of their malignant growth state, and sustained angiogenesis is a prerequisite to the rapid growth of tumors. Based on this, we propose a combination therapy that hinders the unlimited proliferation of tumor cells and destroys tumor blood vessels. Herein, 7-ethyl-10-hydroxycamptothecin (SN38), a typical topoisomerase I inhibitor, was bonded to poly(L-glutamic acid) (PLG) to prepare the nanodrug SN38-NPs, which hinders the unlimited proliferation of tumor cells. A poly(L-glutamic acid)-combretastatin A4 conjugate (CA4-NPs), a representative vascular disrupting agent (VDA), was used to selectively disrupt the tumor blood vessels, cutting off the necessary nutrients and oxygen for the proliferation of tumor cells. In the 4T1 tumor model with an initial volume of about 400 mm3, the combined treatment of SN38-NPs and CA4-NPs showed an excellent cancer treatment effect with a tumor suppression rate of 94.3% and a synergistic interaction (Q = 1.25). Our study provides a new combination therapy approach for chemotherapy, with the hope of further improving the curative effect of anti-cancer therapy.

Effect of Thoracic Epidural Anesthesia on Perioperative Neutrophil Extracellular Trapping Markers in Patients Undergoing Anesthesia and Surgery for Colorectal Cancer: A Randomized, Controlled Trial.

BACKGROUND: Neutrophil extracellular trapping (NETosis) is an immunologic mechanism strongly linked with increased metastatic risk in colorectal cancer. The authors hypothesized that patients who received propofol-epidural anesthesia (PEA) would exhibit decreases in the expression of serum neutrophil myeloperoxidase (MPO) and citrullinated histone H3 (H3Cit) levels compared with patients who received general anesthesia (GA). METHODS: Colorectal cancer surgery patients were randomly assigned to the PEA (n = 30) or GA (n = 30) group. Serum MPO, H3Cit, and metalloproteinase-9 (MMP-9) levels before surgery and 24 h after surgery were measured, and visual analogue scale (VAS) scores were recorded. RESULTS: The patients who received PEA showed decreases in MPO (28.06 ± 11.23 vs 20.54 ± 7.29 ng/ ml; P = 0.004) and H3Cit [3.22 ± 0.86 vs 2.73 ± 0.94 ng/ ml; P = 0.042) 24 h after surgery compared with the patients subjected to GA. In addition, there was no difference in MMP-9 levels (75.98 ± 26.9 vs 73.45 ± 28.4 ng/ ml; P = 0.726). The visual analogue scale scores 2 h and 24 h after operation were significantly lower in PEA group (P < 0.05). The number of postoperative analgesia pump pressings and sufentanil consumptions within 48 h after surgery were significantly lower in the PEA group (P < 0.001). CONCLUSIONS: Propofol-epidural anesthesia reduces the expression of NETosis (MPO and H3Cit) in serum during colorectal cancer surgery. CLINICAL TRIAL REGISTRATION: ChiCTR2200066708 ( www.chictr.org.cn ).

The effect of resveratrol, curcumin and quercetin combination on immuno-suppression of tumor microenvironment for breast tumor-bearing mice.

Resveratrol, curcumin, and quercetin are the secondary metabolites from medicinal food homology plants, that have been proven their potency in cancer treatment. However, the antitumor effect of a single component is weak. So, herein, we designed an antitumor compound named RCQ composed of resveratrol, curcumin, and quercetin. This study examined the effect on tumorigenesis and development of 4T1 breast cancer-bearing mice following administering RCQ by intragastric administration. RCQ increased the recruitment of T cells and reduced the accumulation of neutrophils and macrophages in the tumor microenvironment. Meanwhile, RCQ suppressed the development of tumor-infiltrating lymphocytes into immunosuppressive cell subpopulations, including CD4+ T cells to T helper Type 2 type (Th2), tumor-associated neutrophils (TANs) to the N2 TANs, and tumor-associated macrophages (TAMs) cells to M2 TAMs. RCQ reversed the predominance of immunosuppressive infiltrating cells in the tumor microenvironment and tipped the immune balance toward an immune activation state. In vitro the study showed that RCQ significantly increased reactive oxygen species (ROS), reduce mitochondrial membrane potentials in cancer cells, and modulate pro-apoptotic Bcl-2 family members. In conclusion, RCQ can promote the ROS apoptosis mechanism of tumor cells and alleviate immunosuppression of the tumor microenvironment to enhance the anti-tumor effect.

Super-thin anterolateral thigh flap for reconstruction of the medial plantar artery perforator flap donor site.

BACKGROUND: The medial plantar artery perforator (MPAP) flap is widely used to reconstruct the weight-bearing area of the foot. Traditionally, its donor site is closed using a skin graft, which is associated with several complications, including walking disability. This study aimed to examine our experience with using a super-thin anterolateral thigh (ALT) flap to reconstruct the MPAP flap donor site. METHODS: We examined 10 patients who underwent reconstruction of the MPAP flap donor site using a super-thin ALT flap between August 2019 and March 2021. The vascular pedicle was anastomosed to the proximal end of the medial plantar vessels or the end of the posterior tibial vessels. RESULTS: All reconstruction flaps survived and all patients were satisfied with the aesthetic appearance. No blisters, ulcerations, hyperpigmentation, or contractures occurred. All patients gained protective sensation in the super-thin ALT flap. The average visual analog scale score for the aesthetic appearance of the reconstructed foot was 8.5 ± 0.7 (range, 8-10). All patients were able to ambulate without aids and could wear regular shoes. The average revised Foot Function Index score was 26.4 ± 4.1 (range, 22-34). CONCLUSION: Reconstruction of the MPAP flap donor site using a super-thin ALT flap is reliable and provides satisfactory functional recovery, aesthetic appearance, and protective sensation while minimizing postoperative morbidity.

Corrective surgery for nipple depression in patients with plasmacytic mastitis - A single-center experience.

Background: Plasma cell mastitis (PCM) is a complex breast disease in the clinic. Currently, there are no unified diagnostic criteria for the disease and no standard treatment methods. The effects of hormone, Conventional Chinese medicine and other treatments are uncertain, with long treatment duration and notable side effects. Surgery is the preferred treatment, but the recurrence rate after conventional surgery is very high, which may be related to depression of the nipple. This study aimed to evaluate the efficacy of a novel corrective procedure in patients with cellular mastitis and depressed nipples. Methods: Patients with PCM who received surgical treatment in the Third Medical Center of PLA General Hospital from January 1996 to January 2018 were retrospectively analyzed. According to the presence or absence of nipple depression before surgery, the patients were divided into the nipple depression group and the non-nipple depression group. In the nipple depression group, patients were subdivided into a novel corrective surgery group ("one" suture or half pocket suture) and a conventional corrective surgery group (oil yarn traction valgus correction of nipple depression). Demographic, clinical, therapeutic, and postoperative relapse data were collected and analyzed. Results: Compared with the patients in the non-nipple depression group, patients in the nipple depression group had a significantly higher recurrence risk after surgery (HR = 2.129 95% CI: 1.110-4.083, p = 0.023). Patients who underwent novel corrective surgery had a significantly lower recurrence risk than those who underwent conventional corrective surgery (HR = 0.363 95% CI: 0.150-0.880, p = 0.025). In addition, the novel corrective surgery significantly reduced the postoperative recurrence risk (HR = 0.088 95% CI: 0.009-0.886, p = 0.037). Conclusion: How to correct nipple depression is a critical factor for postoperative recurrence of PCM, and this novel corrective surgery for nipple depression can effectively reduce the postoperative recurrence rate in patients with nipple depression.

Reproductive Toxicity Evaluation of Graphene-Based Tumor Cell Nucleus-Targeting Fluorescent Nanoprobes on Reproduction and Offspring Health.

A new graphene-based fluorescent nanoprobe for tumor cell nucleus (GTTNs) was synthesized in our laboratory that penetrates the cell membrane and particularly targets cancer cell nucleus and displays tremendous potential for clinical applications. Although acute and subacute toxicity studies have been conducted on GTTNs, a primary result could be drawn that GTTNs appear to have almost no acute and subacute toxicity. However, as an important part of safety evaluation, the influences on reproductive and offspring developmental toxicity are still absent. In this study, male mice were injected intravenously with GTTNs, and the survival status, histopathology of the testes and epididymides, proliferation and apoptosis of testicular tissue, and sperm motility of mice were measured. To evaluate the short- and long-term fertility in male mice, different male mice resided with untreated female mice on days 1 and 30 after the end of the last treatment, and the offspring health parameters were assessed by measuring pup numbers, body weight, and organ indexes of the pups. The results indicated that GTTNs-exposed male mice retained good fertility, healthy structure of testes and epididymides, and production of healthy sperm. Meanwhile, there were no significant differences between the offspring and the control group. In consideration of GTTNs with broad prospects for biomedical applications, our results contribute a basis for further understanding of its biosafety.

Endoscopic-assisted locking block modified Krackow technique combined with a V-Y flap for chronic Achilles tendon rupture.

PURPOSE: The purpose of this study was to evaluate the clinical outcomes of the endoscopic-assisted locking block modified Krackow technique with a V-Y flap. The hypothesis was that the minimally invasive technique can reduce wound complications and facilitate early recovery. METHODS: In total, 29 men with chronic Achilles tendon rupture who underwent either minimally invasive technique (n = 13) or open repair (n = 16) at our department between 2013 and 2019 were retrospectively analyzed. The rate of complications, time to return to moderate-intensity exercise, American Orthopedic Foot and Ankle Society ankle hindfoot score, Achilles tendon Total Rupture Score, heel-rise repetitions in 1 min, heel-rise height, and bilateral calf circumference at 6 months, 1 year, and 2 years postoperatively were recorded. RESULTS: All incisions healed primarily in the minimally invasive technique group; however, three patients in the open repair group experienced wound complications. The time to return to moderate-intensity exercise, American Orthopedic Foot and Ankle Society score, Achilles tendon Total Rupture Score, heel-rise repetition ratio, and heel-rise height ratio at 6 months postoperatively in the minimally invasive technique group were significantly better than those in the open repair group. However, it was not significantly different between both groups at 2 years postoperatively. CONCLUSION: Endoscopy allowed scar tissue and adhesions to be removed, allowing the tendon ends to be mobilized out of the small proximal and distal incisions. Minimally invasive technique may result in a lower wound complication incidence and provide better early functional recovery and return to moderate-intensity exercise time than the conventional open procedure in treating chronic Achilles tendon ruptures. CLINICAL TRIAL REGISTRATION: Wuxi Ninth People's Hospital Medical Ethical Committee, LW2021026. LEVEL OF EVIDENCE: III.

A self-activating nanoized vascular disrupting agent for selective anti-tumor therapy.

Vascular disrupting agents (VDAs) have great potential in antitumor therapy, while the efficiency is limited by cardiovascular toxicity. In this study, a self-activating nanoized plinabulin (poly (l-glutamic acid) grafted Azo-Plinabulin, AzoP-NP) was constructed. The AzoP-NPs can selectively be activated to an amino derivative of plinabulin (AmP) by intrinsic tumor hypoxia, disrupting tumor vessels and amplifying hypoxia, whilst be activated by self-amplified tumor hypoxia, then selectively inhibit tumor growth. In 4T1 tumor model, the AzoP-NPs had a selective biodistribution in tumor, as the free AmP in tumors at 24 h after AzoP-NPs treatment was 18.6 fold of that after AmP treatment and significantly higher than that in other tissues. Accordingly, AzoP-NPs resulted in no obvious acute cardiovascular toxicity (plasma von Willebrand factor in PBS, AzoP-NPs and AmP group: 143.1, 184.0 and 477.6 ng/mL) and a significantly stronger tumor inhibition than AmP. And the sustained release of drug in AzoP-NPs led to a higher maximum tolerated dose (MTD) (MTD of AzoP-NPs and AmP: > 80 vs 20 mg/kg). In addition, AzoP-NPs amplified tumor hypoxic, and synergized the anti-tumor effect of Tirapazamine (TPZ), a hypoxia-activated drug in clinical trials, with an inhibition rate of 97.7% and Q value of 1.89. Therefore, our findings provide new insights into next generation VDAs and their application in tumor therapy.

Reconstruction of complex plantar forefoot defects using free tissue flaps combined with contralateral instep thick skin grafts.

PURPOSE: To evaluate the clinical efficacy of using free tissue flap combined with contralateral instep thick plantar skin in reconstructing complex plantar forefoot defects. METHODS: During the past 8 years, 15 patients, aged 25-60 years, with defects in the soft-tissue and composite bone of the forefoot were treated. Their defects were caused by trauma. These defects were all located on the plantar forefoot. The free tissue flaps transposed to reconstruct defects were anterolateral thigh flaps, groin flaps, and latissimus dorsi flaps. Flap size varied in width 4-cm and length (6-16 cm). The mean size of flaps was 80.3 cm2. The follow-up period ranged from 12 to 90 months (mean, 25.5 months). RESULTS: Partial flap loss was observed in one anterolateral thigh flap and one latissimus dorsi flap. One patient showed skin graft loss at the defect site, and the wound was re-epithelialized by changing dressings. Hyperkeratosis was not observed in any of the cases. All patients were able to walk near-normally within 2.5 months after surgery, and there was no recurrence of ulceration. CONCLUSION: We advocate using a free tissue flap combined with contralateral instep thick plantar skin for reconstruction of moderate or large complex plantar forefoot defects.

Manipulating Liver Bile Acid Signaling by Nanodelivery of Bile Acid Receptor Modulators for Liver Cancer Immunotherapy.

Gut bacteria and their metabolites influence the immune microenvironment of liver through the gut-liver axis, thus representing emerging therapeutic targets for liver cancer therapy. However, directly manipulating gut microbiota or their metabolites is not practical in clinic since the safety concerns and the complicated mechanism of action. Considering the dysregulated bile acid profiles associated with liver cancer, here we propose a strategy that directly manipulates the primary and secondary bile acid receptors through nanoapproach as an alternative and more precise way for liver cancer therapy. We show that nanodelivery of bile acid receptor modulators elicited robust antitumor immune responses and significantly changed the immune microenvironment in the murine hepatic tumor. In addition, ex vivo stimulation on both murine and patient hepatic tumor tissues suggests the observation here may be meaningful for clinical practice. This study elucidates a novel and precise strategy for liver cancer immunotherapy.

High-performance MoOx/n-Si heterojunction NIR photodetector with aluminum oxide as a tunneling passivation interlayer.

The most effective and potential approach to improve the performance of heterojunction photodetectors is to obtain favorable interfacial passivation by adding an insertion layer. In this paper, MoOx/Al2O3/n-Si heterojunction photodetectors with excellent photocurrents, responsivity and detectivity were fabricated, in which alumina acts as a tunneling passivation layer. By optimizing the post-annealing treatment temperature of the MoOxand the thickness of the ultra-thin Al2O3, the photodetector achieved a ratio of photocurrent to dark current of 3.1 × 105, a photoresponsivity of 7.11 A W-1(@980 nm) and a detective of 9.85 × 1012Jones at -5 V bias. Besides, a self-driven response of 0.17 A W-1and a high photocurrent/dark current ratio of 2.07 × 104were obtained. The result demonstrated that optimizing the interface of heterojunctions is a promising way to obtain a heterojunction photodetector with high-performance.