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BACKGROUND: With the further development of minimally invasive concepts, unicompartmental knee arthroplasty has become an important treatment for osteoarthritis of the knee; however, early postoperative pain adversely affects the recovery process, so effective analgesic measures are necessary. Femoral nerve block and cocktail therapy are common analgesic methods for unicompartmental knee arthroplasty, but there is a lack of studies confirming the anOBJECTIVE: To investigate the analgesic effect of cocktail therapy combined with femoral nerve block in unicompartmental knee arthroplasty. METHODS: One hundred patients who received unicompartmental knee arthroplasty from October 2021 to January 2023 were selected as the study subjects. They were divided into a control group (n=50) and a study group (n=50) using a random number table method. The femoral nerve block was used in the control group, while cocktail therapy combined with femoral nerve block was used in the study group during unicompartmental knee arthroplasty. Postoperative analgesia effect, analgesic frequency of dezocine injection within 2 days after surgery, motion range of affected knee joint, KSS function scores, and the occurrence of postoperative adverse reactions were compared between the two groups. RESULTS AND CONCLUSION: (1) Visual analog scale scores in the study group were lower than those in the control group at 12, 24, and 48 hours after surgery (P < 0.05). (2) The analgesic frequency of dezocine in the study group was less than that in the control group within 2 days after surgery (P < 0.05). (3) The motion range in the study group was higher than that in the control group 1 and 3 days after surgery (P < 0.05). On day 14 after surgery, there was no significant difference in motion range between the two groups (P > 0.05). (4) The knee KSS score in the study group was higher than that in the control group at 2 weeks after surgery (P < 0.05). There was no statistically significant difference in knee KSS scores between the two groups from 6 weeks to 6 months after surgery (P > 0.05). (5) The difference in the occurrence of adverse reactions within 14 days after surgery was not significant between the two groups (P > 0.05). (6) These results show that the use of cocktail therapy combined with femoral nerve block in unicompartmental knee arthroplasty can effectively reduce postoperative pain, improve the analgesic effect, reduce the frequency of analgesic drugs, and improve motion range of the early affected knee joint of patients. [ABSTRACT FROM AUTHOR]

Starvation therapy aims to "starve" tumor cells by cutting off their nutritional supply. However, due to the complex and varied energy metabolism of tumors, targeting a single nutrient supply often fails to yield significant therapeutic benefits. This study proposes a tumor energy cocktail therapy that combines metformin, an oxidative phosphorylation inhibitor, with 2-deoxy- d -glucose (2-DG), a glycolysis inhibitor, to target tumor cells. To minimize the dosage of both drugs, we have developed a drug delivery strategy that prepared metformin as a nanoderivative, denoted as MA-dots. These MA-dots not only preserve the antitumor properties of metformin but also serve as a targeted delivery platform for 2-DG, ensuring its direct reach to the tumor site. Upon reaching the acidic tumor environment, the composite disintegrates, releasing 2-DG to inhibit glycolysis by targeting hexokinase 2 (HK2), the key enzyme in glycolysis, while MA-dots inhibit mitochondrial OXPHOS. This dual action significantly reduces ATP production in tumor cells, leading to apoptosis. In human lung tumor cells, the half-maximal inhibitory concentration (IC 50) of 2-DG@MA-dots was significantly lower than that of either metformin or 2-DG alone, showing a nearly 100-fold and 30-fold reduction in IC 50 values to 11.78 µg mL−1, from 1159 µg mL−1 and 351.20 µg mL−1, respectively. In studies with A549 tumor-bearing mice, the combination of low-dose 2-DG and metformin did not impede tumor growth, whereas 2-DG@MA-dots markedly decreased tumor volume, with the mean final tumor volume in the combination treatment group being approximately 89 times greater than that in the 2-DG@MA-dot group. Metformin is a promising antitumor agent capable of modulating mitochondrial oxidative phosphorylation to inhibit cancer growth. However, its antitumor efficacy is limited when used alone due to compensatory energy mechanisms. Hence, we introduced glycolysis inhibitor 2-deoxy- d -glucose (2-DG) to inhibit an alternative tumor energy pathway. In our study, we developed a drug delivery strategy using metformin-derived nanomedicine (MA-dots) to load 2-DG. This approach enables the co-delivery of both drugs and their synergistic effect at the tumor site, disrupting both energy pathways and introducing an innovative "energy cocktail therapy". [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: The incidence and mortality of lung cancer are continuously rising in recent years. Mitochondrial energy metabolism malfunction is found to be crucial in cancer proliferation and bioenergetic reprogramming, especially for lung cancer. In this study, we attempted to use mitochondrial-targeted drug therapy to change the energy metabolism pattern of cancer cells to inhibit the development of lung cancer, and investigated its mechanism of action and key targets through multi-omics studies. Methods: In this study, we established the in vivo tumor mouse mode, treated mice with multiple mitochondrial-targeted drug combinations and DDP, severally. Then, we investigated the differences between the 7-drug group with the control group and the DDP treatment group by transcriptomics, proteomics and metabolomics to find the therapeutic targets. Results: We found that mitochondria-targeting drug cocktail therapy, especially the 7-drug regimen, effectively improved mitochondrial metabolism, changed energy supply patterns in lung cancer cells, significantly increased NK cells in tumor tissues, and decreased tumor markers in plasma. Multi-omics analysis informed that the combination of 7-drug could up-regulate mitochondrial oxidative phosphorylation, ATP synthesis and autophagy related genes, and down-regulate proliferation and immune-related genes compared with the control group. By further mapping the protein interaction network, we identified a key target for 7-drug therapy to reverse tumor metabolic reprogramming and validated it in metabolomics. Conclusions: Mitochondrial-targeted drug cocktail therapy can effectively inhibit the occurrence and development of tumors, through the reprogramming of energy metabolism and the increase in immune cells in tumor tissues. Thus, we provide a novel approach for the treatment of lung cancer and present evidence-based clues for the combined use of targeted mitochondrial drugs. [ABSTRACT FROM AUTHOR]

The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) has driven us to explore alternative treatments for the limitation of antimicrobial agents. Lytic phages are considered a promising alternative treatment for CR-hvKP infection. In this study, we reported three novel lytic phages, vB_KpnA_SCNJ1-Z, vB_KpnS_SCNJ1-C, and vB_KpnM_SCNJ1-Y, against a CR-hvKP strain SCNJ1, and they possess genomes of double-stranded DNA with a size of 43,428 bp, 46,039 bp, and 50,360 bp, respectively. Phylogenetic analysis demonstrated that vB_KpnA_SCNJ1-Z belongs to the family Autographiviridae within the class Caudoviricetes, while vB_KpnS_SCNJ1-C and vB_KpnM_SCNJ1-Y are unclassified Caudoviricetes. The phages showed a narrow host range only lysing 1 of 50 tested clinical bacterial strains. The one-step growth curves and stability results showed that the phages displayed relatively short latency periods, with broad pH (pH 3-14) and thermal stabilities (20–60°C). The phages showed significant inhibition of the biofilm formation by SCNJ1 and strong antibacterial activity in vitro. In the mouse model, we demonstrated that administration of a single phage or phage cocktail significantly reduced bacteria loads in the lung, liver, and spleen, and effectively rescued mice from the infection of the SCNJ1 strain, with a survival rate of 70-80%. These findings suggested the three phages have great potential as an alternative therapy with favorable stability and strong antibacterial activity both in vivo and in vitro for the treatment of CR-hvKP infection.

A high-fat diet (HFD) is a major risk factor for cardiovascular diseases. Many pure compounds have been demonstrated to be effective in treating cardiovascular diseases. In this study, we investigated the alleviating effects of oral ovatodiolide and antcin K (OAK) supplements on HFD-induced cardiovascular dysfunction in apolipoprotein E (ApoE)-knockout mice. Cardiovascular dysfunction was induced in ApoE-knockout mice by feeding them an HFD for 12 weeks. The degree of cardiovascular dysfunction was assessed through echocardiography, hematological and biochemical analyses, and immunofluorescence and immunohistochemical staining. The HFD-fed mice exhibited cardiovascular dysfunction—abnormal blood biochemical index. The arterial wall tissue exhibited the marked deposition of lipids, upregulated expression of vascular cell adhesion molecule-1 and CD36 receptors, and downregulated expression of the ABCA1 receptor. Macrophages isolated from the peritoneal cavity of the mice exhibited increased levels of lipid accumulation, reactive oxygen species, and CD11b expression but reduced mitochondrial membrane potential. The expression of superoxide dismutase 2 was downregulated and that of tumor necrosis factor-α was upregulated in the myocardial tissue. Oral OAK supplements twice a day for 12 weeks significantly mitigated HFD-induced cardiovascular dysfunction in the experimental mice. Oral OAK supplements appear to be a promising strategy for treating HFD-induced cardiovascular dysfunction. The underlying mechanisms may involve the reduction of lipid accumulation in the artery and oxidative stress and inflammation in the cardiovascular tissue. [ABSTRACT FROM AUTHOR]

Objective: To compare effectiveness and safety of intravesical therapy (sodium hyaluronate and chondroitin sulphate) Ialuril versus cocktail therapy for treatment of interstitial cystitis (IC). Materials and methods: Prospective study from March 2013 till August 2019 including all IC patients presented to our urology clinic. All IC patients underwent basic workup including urine test, urodynamic test and gynaecological/genital exam. Postoperatively, all patients received intravesical therapy. Patients were randomly allocated to either cocktail therapy (NaOH + heparin + lidocaine) or Ialuril (Sodium hyaluronate and chondroitin sulphate) therapy as intravesical seven cycles. The primary outcome was therapy effectiveness using Interstitial Cystitis Problem Index (ICPI) and Interstitial Cystitis Symptom Index (ICSI) improvement post therapy. Secondary outcome were for complications and compliance. Results: Total of 32 patients were included (6 males, 26 females) with mean age of 43 years (24–72 years), mean follow-up 36 months (15–72 months). Cocktail intravesical therapy was used in 21 patients while 11 patients received Ialuril. All patients showed improvement on their ICSI and ICPI scores post therapy from their baseline. Statistical analysis showed no significant difference between both groups regarding improvement in ICSI and ICPI index with p -value = 0.552 and p = 0.79, respectively. Infection and non-compliance is significantly high in the cocktail arm p = 0.004, p = 0.027 Conclusions: Intravesical cocktail therapy was equally effective as Ialuril in treating IC. Ialuril was preferred over cocktail therapy because of lower side effect; when considering ulcerative IC subgroup, we need large randomised controlled trials to compare therapy benefits. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a deadly hematological malignancy characterized by oncogenic translational addiction that results in over-proliferation and apoptosis evasion of leukemia cells. Various chemo- and targeted therapies aim to reverse this hallmark, but most show only modest efficacy. Here we report a single oral pill containing a low-dose triple small molecule-based cocktail, a highly active anti-cancer therapy (HAACT) with unique mechanisms that can effectively control AML. The cocktail comprises oncogenic translation inhibitor HHT, drug efflux pump P-gpi ENC and anti-apoptotic protein Bcl-2i VEN. Mechanistically, the cocktail can potently kill both leukemia stem cells (LSC) and bulk leukemic cells via co-targeting oncogenic translation, apoptosis machinery, and drug efflux pump, resulting in deep and durable remissions of AML in diverse model systems. We also identified EphB4/Bcl-xL as the cocktail response biomarkers. Collectively, our studies provide proof that a single pill containing a triple combination cocktail might be a promising avenue for AML therapy.

CD19 chimeric antigen receptor T-cell (CAR-T) therapy is efficacious for refractory/relapsed (R/R) B-cell hematological malignancies, yet relapse due to CD19 antigen escape remains a challenge. Our trial explored simultaneous targeting of multiple B-cell antigens as a therapeutic approach that may reduce the risk of relapse. We tested the safety and efficacy of CAR19/22 T-cell cocktail therapy including murinized and humanized products among patients with R/R aggressive B-cell lymphoma. In the group that received the humanized product, 11/12 (91.7%) patients achieved an objective response, including 9/12 (75%) complete responses (CRs) by day 28. The overall response rate and CR rate in the murinized group was 92.9% (13/14) and 42.9% (6/14), respectively. Nine of 12 (75%) patients in the humanized group maintained CR at month 3 following infusion, compared to 5/14 patients (35.7%) in the murinized group. Progression-free survival (PFS) was more favorable in the humanized compared to the murinized group. Most patients had mild cytokine release syndrome (CRS) (grade 1–2) in both groups. This study demonstrates that CAR19/22 T-cell cocktail therapy is safe and effective for R/R B-cell lymphoma and that patients treated with a humanized CAR-T exhibited better efficacy compared to patients treated with a murinized CAR-T therapy. [ABSTRACT FROM AUTHOR]

A high-fat diet (HFD) is a major risk factor for cardiovascular diseases. Many pure compounds have been demonstrated to be effective in treating cardiovascular diseases. In this study, we investigated the alleviating effects of oral ovatodiolide and antcin K (OAK) supplements on HFD-induced cardiovascular dysfunction in apolipoprotein E (ApoE)-knockout mice. Cardiovascular dysfunction was induced in ApoE-knockout mice by feeding them an HFD for 12 weeks. The degree of cardiovascular dysfunction was assessed through echocardiography, hematological and biochemical analyses, and immunofluorescence and immunohistochemical staining. The HFD-fed mice exhibited cardiovascular dysfunction—abnormal blood biochemical index. The arterial wall tissue exhibited the marked deposition of lipids, upregulated expression of vascular cell adhesion molecule-1 and CD36 receptors, and downregulated expression of the ABCA1 receptor. Macrophages isolated from the peritoneal cavity of the mice exhibited increased levels of lipid accumulation, reactive oxygen species, and CD11b expression but reduced mitochondrial membrane potential. The expression of superoxide dismutase 2 was downregulated and that of tumor necrosis factor-α was upregulated in the myocardial tissue. Oral OAK supplements twice a day for 12 weeks significantly mitigated HFD-induced cardiovascular dysfunction in the experimental mice. Oral OAK supplements appear to be a promising strategy for treating HFD-induced cardiovascular dysfunction. The underlying mechanisms may involve the reduction of lipid accumulation in the artery and oxidative stress and inflammation in the cardiovascular tissue.

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system is a powerful gene editing tool originated from prokaryotes. The modern CRISPR/Cas9 system allows high-throughput genetic screening to be carried out in vitro and in vivo. The high efficacy and flexibility of CRISPR/Cas9 system allows identification of hepatocellular carcinoma (HCC) related genes in the past decades. Numerous efforts have been applied in the past to improve this system, such as off-target improvement, gRNA efficiency enhancement, and modified Cas9 nuclease for performing visionary base editor screens and epigenetic screens. With these merits, the CRISPR/Cas9 offers tremendous opportunities in various biomedical research and clinical application. Recently, the use of the CRISPR/Cas9 system has also been combined with different technologies, including single-cell sequencing and machine learning, to further understand HCC pathogenesis and explore its utility in gene therapy. This review provides a summary of HCC carcinogenesis CRISPR/Cas9 screens conducted in recent years with different genetic contexts, epidemiological backgrounds, and progression of HCC. Furthermore, this review also provides insight in the CRISPR/Cas9 potentials, current obstacles, and improvement of this system for its future utility in cocktail therapies.

Abstract Background Mono-therapeutic modality has limitations in combating metastatic lesions with complications. Although emerging immunotherapy exhibits preliminary success, solid tumors are usually immunosuppressive, leading to ineffective antitumor immune responses and immunotherapeutic resistance. The rational combination of several therapeutic modalities may potentially become a new therapeutic strategy to effectively combat cancer. Results Poly lactic-co-glycolic acid (PLGA, 50 mg) nanospheres were constructed with photothermal transduction agents (PTAs)-Prussian blue (PB, 2.98 mg) encapsulated in the core and chemotherapeutic docetaxel (DTX, 4.18 mg)/ immune adjuvant-imiquimod (R837, 1.57 mg) loaded in the shell. Tumor cell membranes were further coated outside PLGA nanospheres (designated “M@P-PDR”), which acted as “Nano-targeted cells” to actively accumulate in tumor sites, and were guided/monitored by photoacoustic (PA)/ magnetic resonance (MR) imaging. Upon laser irradiation, photothermal effects were triggered. Combined with DTX, PTT induced in situ tumor eradication. Assisted by the immune adjuvant R837, the maturation rate of DCs increased by 4.34-fold compared with that of the control. In addition, DTX polarized M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, relieving the immunosuppressive TME. The proportion of M2-TAMs decreased from 68.57% to 32.80%, and the proportion of M1-TAMs increased from 37.02% to 70.81%. Integrating the above processes, the infiltration of cytotoxic T lymphocytes (CTLs) increased from 17.33% (control) to 35.5%. Primary tumors and metastasis were significantly inhibited when treated with “Nano-targeted cells”-based cocktail therapy. Conclusion “Nano-targeted cells”-based therapeutic cocktail therapy is a promising approach to promote tumor regression and counter metastasis/recurrence. Graphical Abstract

Objective To analyze the results of unicompartmental knee arthroplasty (UKA) in patients with single compartment of knee osteoarthritis, and to evaluate the clinical outcomes and safety with different analgesias. Methods Totally 45 cases were recruited from January 2017 to December 2019 including 18 males and 27 females. The mean age was (63.41±1.19) year-old. They were divided into three groups with 15 in each.Patients in group A received cocktail treatment after surgery. Patients in group B received adductor canal blockade treatment by ultrasound guide after surgery. and those in group C received both cocktail treatment and adductor canal blockade treatment by ultrasound guide after surgery. VAS score and KSS score were compared and analyzed according to postoperative follow-up results. Results VAS scores and KSS scores of the three groups before surgery were not different but VAS scores and KSS scores of the two groups were significantly reduced after treatment (P＜0.05). Post-operative VAS score and KSS score were significantly different between the two groups (P＜0.05). Conclusions As an effective final treatment for single compartment of knee osteoarthritis, UKA is the most effective treatment in the early and middle stages of knee preserving surgery. Combining cocktail treatment and adductor canal blockade treatment by ultrasound guide after surgery can provide a safe post-operative analgesia for unicompartmental knee arthroplasty.

Abstract Background Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus with a high mutation rate. Importantly, several currently circulating SARS-CoV-2 variants are associated with loss of efficacy for both vaccines and neutralizing antibodies. Methods We analyzed the binding activity of six highly potent antibodies to the spike proteins of SARS-CoV-2 variants, assessed their neutralizing abilities with pseudovirus and authentic SARS-CoV-2 variants and evaluate efficacy of antibody cocktail in Delta SARS-CoV-2-infected hamster models as prophylactic and post-infection treatments. Results The tested RBD-chAbs, except RBD-chAb-25, maintained binding ability to spike proteins from SARS-CoV-2 variants. However, only RBD-chAb-45 and -51 retained neutralizing activities; RBD-chAb-1, -15, -25 and -28 exhibited diminished neutralization for all SARS-CoV-2 variants. Notably, several cocktails of our antibodies showed low IC50 values (3.35–27.06 ng/ml) against the SARS-CoV-2 variant pseudoviruses including United Kingdom variant B.1.1.7 (Alpha), South Africa variant B.1.351 (Beta), Brazil variant P1 (Gamma), California variant B.1.429 (Epsilon), New York variant B.1.526 (Iota), and India variants, B.1.617.1 (Kappa) and B.1.617.2 (Delta). RBD-chAb-45, and -51 showed PRNT50 values 4.93–37.54 ng/ml when used as single treatments or in combination with RBD-chAb-15 or -28, according to plaque assays with authentic Alpha, Gamma and Delta SARS-CoV-2 variants. Furthermore, the antibody cocktail of RBD-chAb-15 and -45 exhibited potent prophylactic and therapeutic effects in Delta SARS-CoV-2 variant-infected hamsters. Conclusions The cocktail of RBD-chAbs exhibited potent neutralizing activities against SARS-CoV-2 variants. These antibody cocktails are highly promising candidate tools for controlling new SARS-CoV-2 variants, including Delta.

The Streptococcus mutans (S. mutans) phage, as one of the principal pathogenic bacteria of dental caries, is a main cause of the formation and development of dental caries due to its overproliferation in dental plaque biofilms. Bacterial viruses, also known as bacteriophages, have the capability of specifically infecting bacteria and effectively degrading bacterial biofilms. S. mutans phages, therefore, may prevent and control caries. Therapy based on phages has been applied in many fields, but the application of S. mutans phages in caries remains exploratory. This article will review the research progress of S. mutans phages in clinical caries prevention, aiming to provide a new idea for the clinical prevention of caries. The results of the literature review show that the living bacteriophage system has the advantages of high specificity, high affinity and good safety. However, due to its unstable structure, it can be processed into a more stable formulation by freeze-drying, spray drying, adding stability enhancers, or incorporating bacteriophages into ointments, biodegradable polymer matrices or particles to a certain extent to improve stability. The lysozyme produced by phages can digest the bacterial cell wall and release the assembled phage particles, which effectively cleave biofilms. In addition, the antigen binding fragment library for cariogenic pathogens was screened by phage display technology, and the purpose of caries prevention and treatment was achieved by passive immunization of antigen binding fragments. However, the host range of bacteriophages is narrow, so this kind of problem can be overcome by phage combined with traditional therapy or other drug use or cocktail therapy with multiple phages in clinical caries prevention and control.

Background: Mono-therapeutic modality has limitations in combating metastatic lesions with complications. Although emerging immunotherapy exhibits preliminary success, solid tumors are usually immunosuppressive, leading to ineffective antitumor immune responses and immunotherapeutic resistance. The rational combination of several therapeutic modalities may potentially become a new therapeutic strategy to effectively combat cancer. Results: Poly lactic-co-glycolic acid (PLGA, 50 mg) nanospheres were constructed with photothermal transduction agents (PTAs)-Prussian blue (PB, 2.98 mg) encapsulated in the core and chemotherapeutic docetaxel (DTX, 4.18 mg)/ immune adjuvant-imiquimod (R837, 1.57 mg) loaded in the shell. Tumor cell membranes were further coated outside PLGA nanospheres (designated "M@P-PDR"), which acted as "Nano-targeted cells" to actively accumulate in tumor sites, and were guided/monitored by photoacoustic (PA)/ magnetic resonance (MR) imaging. Upon laser irradiation, photothermal effects were triggered. Combined with DTX, PTT induced in situ tumor eradication. Assisted by the immune adjuvant R837, the maturation rate of DCs increased by 4.34-fold compared with that of the control. In addition, DTX polarized M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, relieving the immunosuppressive TME. The proportion of M2-TAMs decreased from 68.57% to 32.80%, and the proportion of M1-TAMs increased from 37.02% to 70.81%. Integrating the above processes, the infiltration of cytotoxic T lymphocytes (CTLs) increased from 17.33% (control) to 35.5%. Primary tumors and metastasis were significantly inhibited when treated with "Nano-targeted cells"-based cocktail therapy. Conclusion: "Nano-targeted cells"-based therapeutic cocktail therapy is a promising approach to promote tumor regression and counter metastasis/recurrence. [ABSTRACT FROM AUTHOR]

Background The treatment of keloids is both challenging and controversial. Until now, there is no definitive treatment modality for keloids. To determine the efficacy and safety of an intralesional cocktail therapy, including bleomycin compared to corticosteroid injection method on the treatment of keloid scars. Methods A retrospective chart review was performed for 35 patients diagnosed with keloids. The cocktail therapy regimen consisted of bleomycin, 1% lidocaine, verapamil, and triamcinolone, which was further diluted with 1 mL of normal saline. In group B, 1mL of triamcinolone acetonide was injected into the lesion. Results for a total of 35 patients included in this study were evaluated according to their therapeutic responses and complications six months after the last session. Results Analyzing the outcomes of the patients treated with a cocktail regimen (group A), it was found that 87% showed favorable therapeutic responses (scar thickness

CD19 chimeric antigen receptor T-cell (CAR-T) therapy is efficacious for refractory/relapsed (R/R) B-cell hematological malignancies, yet relapse due to CD19 antigen escape remains a challenge. Our trial explored simultaneous targeting of multiple B-cell antigens as a therapeutic approach that may reduce the risk of relapse. We tested the safety and efficacy of CAR19/22 T-cell cocktail therapy including murinized and humanized products among patients with R/R aggressive B-cell lymphoma. In the group that received the humanized product, 11/12 (91.7%) patients achieved an objective response, including 9/12 (75%) complete responses (CRs) by day 28. The overall response rate and CR rate in the murinized group was 92.9% (13/14) and 42.9% (6/14), respectively. Nine of 12 (75%) patients in the humanized group maintained CR at month 3 following infusion, compared to 5/14 patients (35.7%) in the murinized group. Progression-free survival (PFS) was more favorable in the humanized compared to the murinized group. Most patients had mild cytokine release syndrome (CRS) (grade 1–2) in both groups. This study demonstrates that CAR19/22 T-cell cocktail therapy is safe and effective for R/R B-cell lymphoma and that patients treated with a humanized CAR-T exhibited better efficacy compared to patients treated with a murinized CAR-T therapy.

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus with a high mutation rate. Importantly, several currently circulating SARS-CoV-2 variants are associated with loss of efficacy for both vaccines and neutralizing antibodies. Methods: We analyzed the binding activity of six highly potent antibodies to the spike proteins of SARS-CoV-2 variants, assessed their neutralizing abilities with pseudovirus and authentic SARS-CoV-2 variants and evaluate efficacy of antibody cocktail in Delta SARS-CoV-2-infected hamster models as prophylactic and post-infection treatments. Results: The tested RBD-chAbs, except RBD-chAb-25, maintained binding ability to spike proteins from SARS-CoV-2 variants. However, only RBD-chAb-45 and -51 retained neutralizing activities; RBD-chAb-1, -15, -25 and -28 exhibited diminished neutralization for all SARS-CoV-2 variants. Notably, several cocktails of our antibodies showed low IC50 values (3.35–27.06 ng/ml) against the SARS-CoV-2 variant pseudoviruses including United Kingdom variant B.1.1.7 (Alpha), South Africa variant B.1.351 (Beta), Brazil variant P1 (Gamma), California variant B.1.429 (Epsilon), New York variant B.1.526 (Iota), and India variants, B.1.617.1 (Kappa) and B.1.617.2 (Delta). RBD-chAb-45, and -51 showed PRNT50 values 4.93–37.54 ng/ml when used as single treatments or in combination with RBD-chAb-15 or -28, according to plaque assays with authentic Alpha, Gamma and Delta SARS-CoV-2 variants. Furthermore, the antibody cocktail of RBD-chAb-15 and -45 exhibited potent prophylactic and therapeutic effects in Delta SARS-CoV-2 variant-infected hamsters. Conclusions: The cocktail of RBD-chAbs exhibited potent neutralizing activities against SARS-CoV-2 variants. These antibody cocktails are highly promising candidate tools for controlling new SARS-CoV-2 variants, including Delta. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although cocktail therapy is widely used to relieve pain after total knee arthroplasty, the analgesic effect of different combination schemes has not been fully confirmed. OBJECTIVE: To observe the efficacy of cocktail therapy on analgesia after total knee arthroplasty with enhanced recovery after surgery program. METHODS: Sixty patients with severe knee osteoarthritis who underwent unilateral total knee arthroplasty at Tianjin Hospital from January to May 2019 were enrolled. According to the principle of double-blind randomization, they were divided into two groups, 30 cases in each group. Patients in the trial group were injected with cocktail formula drugs around the joints in the operation, while patients in the control group did not receive any treatment. Static pain visual analogue scale scores of knee joints at 6, 12, 24, 48, and 72 hours, the maximum flexion of the knee joint at 48 and 72 hours, the initial time of the straight legraising, and postoperative opioid remedy analgesia rate and postoperative complications were compared between the two groups. RESULTS AND CONCLUSION: (1) The visual analogue scale scores of the trial group were significantly lower than those of the control group at 6 and 12 hours after operation (both P < 0.001), and the postoperative analgesic rate of opioids was significantly lower in the trial group than that of the control group (P < 0.001). (2) There were no statistically significantly differences in the preoperative general data, visual analogue scale scores at 24, 48, and 72 hours, knee maximum flexion at 48 and 72 hours, the time of the straight leg-raising, and postoperative complications (both P > 0.05). (3) The results indicate that cocktail therapy in total knee arthroplasty is safe and effective for early postoperative analgesia with enhanced recovery after surgery program. [ABSTRACT FROM AUTHOR]

Chenhao Zhang,1 Yanjing Zang,2 Qin Song,3 Hongxuan Li,1 Lei Hu,1 Weidong Zhao,3 Shanshan Feng,1 Fang Gu,4 FengLi Zhao,1 Chunliang Zhang11Department of Neurology, The Second Hospital of Baoding City, Baoding, Hebei 071051, People’s Republic of China; 2Department of Geriatric, The Second Hospital of Baoding City, Baoding, Hebei 071051, People’s Republic of China; 3Second Neurology Department, The Second Hospital of Baoding City, Baoding, Hebei, 071051, People’s Republic of China; 4Fifth Department of Internal Medicine, Baoding Children’s Hospital, Baoding, Hebei 071051, People’s Republic of ChinaObjective: To explore the efficacy and safety of “cocktail therapy” in Parkinson’s disease with dementia (PDD).Patients and methods: Sixty patients with PDD were randomly assigned to the test group (n=30) and a control group (n=30). The control group received 10 mg of donepezil hydrochloride tablets orally, once a day. The test group was treated with a “cocktail therapy”, which consisted of 10 mg of donepezil hydrochloride tablets taken orally, once a day; 200 mg of dl-3n-butylphthalide soft capsules taken orally, 15 mins before each meal, three times daily; 800 mg of oxiracetam capsules taken orally, three times daily; and 80 mg of Ginkgo biloba extract tablets taken orally, three times daily. Treatment was administered for six months. The Montreal cognitive assessment scale (MoCA), Blessed-Roth dementia scale, and Clinical Dementia Rating Scale sum of boxes (CDR-SB) were used before treatment and on the third and sixth month after treatment. Adverse events were also monitored.Results: There were no statistical differences in MoCA, CDR-SB, or Blessed-Roth dementia scale scores between the two groups before treatment. MoCA scores of the test group at six months were significantly higher than those before the treatment and at three months, while both the Blessed-Roth and CDR-SB scores were significantly lower than those before treatment and at three months (p0.05) between the test group (16.67%) and the control group (13.33%) in the rate of abnormal liver function after treatment.Conclusion: Treatment with “cocktail therapy” was safe and improved the conditions of patients with PDD, as well as the quality of life of the patients.Keywords: cocktail therapy, Parkinson’s disease with dementia, efficacy, donepezil hydrochloride, cocktail therapy

Huanglongbing (HLB) is a destructive citrus bacterial disease caused by Candidatus Liberibacter asiaticus (Ca.Las) and cannot be cured by current pesticides. Root lesion and Tylenchulus semipenetrans juveniles were observed in HLB-affected citrus tree roots. We hypothesize that root treatment with fosthiazate (FOS) and Cupric-Ammonium Complex (CAC) will improve the root growth and inhibit HLB. CAC is a broad spectrum fungicide and can promote growth of crops. FOS kills Tylenchulus semipenetrans and protects roots from damage by harmful bacteria such as Ca.Las. After 90 days of combination treatment of FOS and CAC through root drenches, the citrus grew new roots and its leaves changed their color to green. The inhibition rate of Ca.Las reached more than 90%. During treatment process, the chlorophyll content and the root vitality increased 396 and 151%, respectively, and starch accumulation decreased by 88%. Transmission electron microscopy (TEM) and plant tissue dyeing experiments showed that more irregular swollen starch granules existed in the chloroplast thylakoid system of the HLB-infected leaves. This is due to the blocking of their secretory tissue by starch. TEM and flow cytometry experiments in vitro showed the synergistic effects of FOS and CAC. A transcriptome analysis revealed that the treatment induced the differential expression of the genes which involved 103 metabolic pathways. These results suggested that the cocktail treatment of FOS and CAC may effectively kill various pathogens including Ca.Las on citrus root and thus effectively control HLB.

Huanglongbing (HLB) is a destructive citrus bacterial disease caused by Candidatus Liberibacter asiaticus (Ca.Las) and cannot be cured by current pesticides. Root lesion and Tylenchulus semipenetrans juveniles were observed in HLB-affected citrus tree roots. We hypothesize that root treatment with fosthiazate (FOS) and Cupric-Ammonium Complex (CAC) will improve the root growth and inhibit HLB. CAC is a broad spectrum fungicide and can promote growth of crops. FOS kills Tylenchulus semipenetrans and protects roots from damage by harmful bacteria such as Ca.Las. After 90 days of combination treatment of FOS and CAC through root drenches, the citrus grew new roots and its leaves changed their color to green. The inhibition rate of Ca.Las reached more than 90%. During treatment process, the chlorophyll content and the root vitality increased 396 and 151%, respectively, and starch accumulation decreased by 88%. Transmission electron microscopy (TEM) and plant tissue dyeing experiments showed that more irregular swollen starch granules existed in the chloroplast thylakoid system of the HLB-infected leaves. This is due to the blocking of their secretory tissue by starch. TEM and flow cytometry experiments in vitro showed the synergistic effects of FOS and CAC. A transcriptome analysis revealed that the treatment induced the differential expression of the genes which involved 103 metabolic pathways. These results suggested that the cocktail treatment of FOS and CAC may effectively kill various pathogens including Ca.Las on citrus root and thus effectively control HLB. [ABSTRACT FROM AUTHOR]

We investigated the effectiveness of cocktail therapy after arthroscopic rotator cuff repair (ARCR). We evaluated 128 shoulders undergoing ARCR and used block randomization to divide patients into 2 groups in this double-blind trial: The cocktail group received 20 mL of 0.75% ropivacaine, 5 mg of morphine, 0.3 mg of epinephrine, 2 mg of betamethasone, and saline solution to a total of 42 mL, whereas the control group received 20 mL of 0.75% ropivacaine and saline solution to a total of 42 mL. Postoperatively, one of the drug mixtures was injected into the glenohumeral joint, subacromial bursa, suprascapular nerve, and anterior, middle, and posterior parts of the deltoid muscle according to the treatment group. We recorded patients' visual analog scale scores preoperatively and at 4, 8, 16, 24, and 48 hours postoperatively; the number of patients using postoperative diclofenac suppositories and buprenorphine hydrochloride; the number of patients experiencing nausea; the number of patients with infection and delayed wound healing as adverse effects; the surgery time; the retear rate; and passive shoulder range of motion. The cocktail group constituted 64 shoulders (50.0%), with 39 men (60.9%) and 25 women (39.1%); the mean age was 64.2 ± 10.2 years. The control group constituted 64 shoulders (50.0%), with 41 men (64.1%) and 23 women (35.9%); the mean age was 65.2 ± 7.5 years. We found no significant difference in age or sex between the 2 groups. There was also no significant difference in rotator cuff tear size or surgery time between the 2 groups. The visual analog scale scores at 8, 16, and 24 hours postoperatively were significantly lower in the cocktail group. The number of patients using suppositories was also significantly lower in the cocktail group. The number of patients receiving buprenorphine injections tended to be lower in the cocktail group, but the difference was not significant. Nausea occurred in 6.3% of patients in the cocktail group and 15.6% in the control group, but the difference was not significant. No infection or delayed wound healing occurred in either group. There was no significant difference in the retear rate between the 2 groups. Passive anterior elevation at 3 months postoperatively was significantly better in the cocktail group than in the control group. We compared cocktail therapy and ropivacaine after ARCR and found no difference in results except for VAS score at 8, 16, and 24 hours postoperatively and frequency of postoperative suppository use without an apparent risk of infection or a detrimental effect on tendon healing. [ABSTRACT FROM AUTHOR]

BACKGROUND: Steroids have strong anti-inflammatory, anti-emetic and analgesic effects and are widely used in perioperative analgesia. Studies have shown that periarticular injection of steroid-containing cocktail analgesic therapy in knee arthroplasty can relieve postoperative pain, improve knee activity, and reduce complications. However, the other studies show that steroids can increase the risk of postoperative infection, and tendon rupture. Therefore, the safety and efficacy of steroid-containing cocktail periarticular injection in knee arthroplasty is still controversial. OBJECTIVE: To evaluate the safety and efficacy of steroid-containing cocktail periarticular injection after knee arthroplasty by meta-analysis. METHODS: The published literatures were searched on the databases of PubMed/Medline, Cochrane Central Register of Controlled Trials, and EMBASE until April 2019. All randomized controlled trials of topical steroid analgesia after knee arthroplasty were collected and eligible articles were screened. Two researchers independently assessed the risk of bias and methodological quality of included studies by the Cochrane 5.0. The outcome data were extracted and a meta-analysis was conducted by Review Manager 5.2 software. RESULTS AND CONCLUSION: (1) A total of 10 randomized controlled articles involving 820 patients were included. (2) The meta-analysis showed that visual analogue scale score was lower in the steroid group than in the control group at postoperative 1 day [MD=-1.52, 95%CI(-2.94, -0.1 0}, P=0.04]. Motion range was higher in the steroid group than in the control group at postoperative 1, 2, 3, 4 and 5 days [MD=11.57, 95%CI(9.85, 13.30}, P< 0.000 01; MD-9.03, 95%CI(6.67, 11.38}, P< 0.000 01; MD-5.73, 95%CI(0.85, 10.60}, P=0.02; MD-5.53, 95%CI(0.68, 10.38), P=0.03}; MD=5.90, 95%CI(0.87, 10.93), P=0.02]. Morphine use was less in the steroid group than in the control group [MD=-7.94, 95%CI(-14.35, -1.53), P=0.02]. Hospital stay was shorter in the steroid group than in the control group [MD=-<>.98, 95%CI(-1.25, -0.71 ), P < 0.000 01]. Straight leg raising took less time in the steroid group than in the control group [MD=0.65, 95%CI(-0.86, 0.44), P < 0.000 01]. Postoperative C-reactive protein level was lower in the steroid group than in the control group [WMD=-4.82, 95%CI(7.41, 2.23), P=0.000 3]. Knee society score and complication rate were not significantly different between the two groups. (3) To conclude, the periarticular injection of steroid-containing cocktails after knee arthroplasty is safe and effective. [ABSTRACT FROM AUTHOR]

Aim: Lung cancer has a very high incidence rate, and thus, there is an urgent need for novel and effective therapies. Materials & methods: In this study, we proposed a potential treatment option by combining four natural products in liposome systems. Results:In vitro studies indicated that the combination of betulinic acid, parthenolide, honokiol and ginsenoside Rh2 exhibited a synergistic action. When these four natural products were loaded into liposome systems, we observed an increased effect. The relative action was also observed in vivo. The cisplatin group presented obvious kidney damage, whereas both cocktail therapy and cocktail liposome therapy were safer. Conclusion: Therefore, we propose cocktail liposome systems may provide a more efficient and safer treatment for lung cancer. [ABSTRACT FROM AUTHOR]

The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) has driven us to explore alternative treatments for the limitation of antimicrobial agents. Lytic phages are considered a promising alternative treatment for CR-hvKP infection. In this study, we reported three novel lytic phages, vB&#95;KpnA&#95;SCNJ1-Z, vB&#95;KpnS&#95;SCNJ1-C, and vB&#95;KpnM&#95;SCNJ1-Y, against a CR-hvKP strain SCNJ1, and they possess genomes of double-stranded DNA with a size of 43,428 bp, 46,039 bp, and 50,360 bp, respectively. Phylogenetic analysis demonstrated that vB&#95;KpnA&#95;SCNJ1-Z belongs to the family Autographiviridae within the class Caudoviricetes , while vB&#95;KpnS&#95;SCNJ1-C and vB&#95;KpnM&#95;SCNJ1-Y are unclassified Caudoviricetes . The phages showed a narrow host range only lysing 1 of 50 tested clinical bacterial strains. The one-step growth curves and stability results showed that the phages displayed relatively short latency periods, with broad pH (pH 3-14) and thermal stabilities (20-60°C). The phages showed significant inhibition of the biofilm formation by SCNJ1 and strong antibacterial activity in vitro . In the mouse model, we demonstrated that administration of a single phage or phage cocktail significantly reduced bacteria loads in the lung, liver, and spleen, and effectively rescued mice from the infection of the SCNJ1 strain, with a survival rate of 70-80%. These findings suggested the three phages have great potential as an alternative therapy with favorable stability and strong antibacterial activity both in vivo and in vitro for the treatment of CR-hvKP infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fang, Dai, Xiang, Qiu, Yin, Fu, Li and Zhang.)

Acute myeloid leukemia (AML) is a deadly hematological malignancy characterized by oncogenic translational addiction that results in over-proliferation and apoptosis evasion of leukemia cells. Various chemo- and targeted therapies aim to reverse this hallmark, but most show only modest efficacy. Here we report a single oral pill containing a low-dose triple small molecule-based cocktail, a highly active anti-cancer therapy (HAACT) with unique mechanisms that can effectively control AML. The cocktail comprises oncogenic translation inhibitor HHT, drug efflux pump P-gpi ENC and anti-apoptotic protein Bcl-2i VEN. Mechanistically, the cocktail can potently kill both leukemia stem cells (LSC) and bulk leukemic cells via co-targeting oncogenic translation, apoptosis machinery, and drug efflux pump, resulting in deep and durable remissions of AML in diverse model systems. We also identified EphB4/Bcl-xL as the cocktail response biomarkers. Collectively, our studies provide proof that a single pill containing a triple combination cocktail might be a promising avenue for AML therapy. [Display omitted] • P-gp is one of the critical causes of the low efficacy of single-agent HHT in AML. • P-gp inhibitor ENC enhances HHT anti-cancer efficacy both in vitro and in vivo. • The oral triple pill-based cocktail of HHT/ENC/VEN exhibits satisfactory anti-tumor efficacy. • Cocktail reverses oncogenic translation addiction in AML. • EphB4/Bcl-xL could be a potential molecular biomarker of Cocktail response. [ABSTRACT FROM AUTHOR]

The article present a case study of a 36-year-old mother who had a history of the spontaneous abortion of the male fetus gave birth to a 2,800 g male infant who appeared to be healthy. It mentions the newborn metabolic tests showing a negative result for 3-methylglutaconic aciduria. It also mentions that a vitamin cocktail treatment was initiated to rescue mitochondrial respiration.

Macrophages as the main cause of cancer immunosuppression, how to effectively induce macrophage M1 polarization remain the major challenge in lung cancer therapy. Herein, inspired by endogenous reactions, a strategy is proposed to coactivate macrophage M1 polarization by reactive oxygen species (ROS) and nitric oxide (NO) with self-autocatalytic cascade reaction. To enhance the generation of NO and ROS, NO Precursor-Arginine as capping agents for inducing synthesis two kinds of chiral ruthenium nanozyme (D/L-Arginine@Ru). Under the properties of Ru nanozymes through synchronously mimicking the activity of oxidase and nitric oxide synthase (NOS), chiral Ru nanozyme can rapidly generate 1 O 2 and O 2 at first stage, and then catalyze Arginine to produce sufficient NO, thus enhance macrophage M1 polarization to reverse tumor immunosuppression. Moreover, combination the antitumor activity of 1 O 2 , NO, the chiral Ru nanozymes realize the "cocktail therapy" by inducing tumor cell apoptosis as well as ferroptosis. In addition, the chirality influences the bioactivity of Ru nanozymes that L-Arginine@Ru shows the better therapeutic effect with stronger catalytic activity and natural homology. It is hoped the high performance of chiral Ru nanozyme with "cocktail therapy" is an effective therapeutic reagent and can provide a feasible treatment strategy for tumor catalytic therapy., (© 2023 Wiley-VCH GmbH.)

The proliferation and global expansion of multidrug-resistant (MDR) bacteria have deepened the need to develop novel antimicrobials. Antimicrobial peptides (AMPs) are regarded as promising antibacterial agents because of their broad-spectrum antibacterial activity and multifaceted mechanisms of action with non-specific targets. However, if AMPs are to be applied sustainably, knowledge of how they induce resistance in pathogenic bacteria must be mastered to avoid repeating the traditional antibiotic resistance mistakes currently faced. Furthermore, the evolutionary constraints on the acquisition of AMP resistance by microorganisms in the natural environment, such as functional compatibility and fitness trade-offs, inform the translational application of AMPs. Consequently, the shortcut to achieve sustainable utilization of AMPs is to uncover the evolutionary constraints of bacteria on AMP resistance in nature and find the tricks to exploit these constraints, such as applying AMP cocktails to minimize the efficacy of selection for resistance or combining nanomaterials to maximize the costs of AMP resistance. Altogether, this review dissects the benefits, challenges, and opportunities of utilizing AMPs against disease-causing bacteria, and highlights the use of AMP cocktails or nanomaterials to proactively address potential AMP resistance crises in the future. [ABSTRACT FROM AUTHOR]

• A medium-strength complex was formed between P5SB and MB. • The amphiphilic P5SB⊃MB complex assembled into stable vesicles at pH=7.4. • The anti-cancer efficiency of DOX-loaded P5SB⊃MB vesicles was significantly enhanced. • The live-cell imaging property of DOX was maintained after encapsulation. Cocktail therapy is one of the leading approaches for treating some complex diseases. Herein, a pH-triggered supramolecular cocktail drug delivery system assembled by the medium-strength complexes of pillar[5]arene-based Schiff base (P5SB) with methylene blue (MB). Molecular modeling suggest that noncovalent interactions between Schiff base side chain of P5SB and MB were mainly responsible for the stability of the complex. The amphiphilic P5SB⊃MB complex assembled into stable vesicles with an average diameter of 244.1 nm in conventional physiological environment (pH=7.4). Drug loading experiments demonstrated that doxorubicin (DOX) could be efficiently encapsulated into the hollow vesicles, and the drug would be rapidly released under acidic environment (pH=6.0). Moreover, the anti-cancer efficiency of DOX-loaded P5SB⊃MB vesicles was significantly enhanced because of the synergistic effect of P5SB, MB and DOX. Nonetheless, the live-cell imaging property of DOX was maintained after encapsulation. [Display omitted] [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the clinical efficacy of cocktail neuroprotective agents(N6) in treatment of spasm in patient with traumatic spinal cord injury (TSCI). METHODS: 189 patients with TSCI diagnosed by Jinan Military General Hospital from Jan.2013 to Jun.2016 were retrospectively selected and divided into observation group (102 cases) and control group(87 cases) according to the application of cocktail neuroprotective agents(N6). The incidence of spasm of two groups were observed and compared at 2 months and 12 months after injured;for patients stricken by spasm at 2 months after injured, the total effective rate at 12 months after injured were observed and compared. RESULTS: At 2 months and 12 months after injured, the incidence of spasm of the observation group was significantly lower than that of the control group, with statistically significant difference (P ＜ 0.05). 12 months after injured,the total effective rate of the observation group (62.79％, 27/43) was significantly higher than that of the control group(35.85％, 19/53), with statistically significant difference(P ＜0.05). CONCLUSIONS: The cocktail neuroprotective agents(N6) can effectively reduce the incidence of spasm in patient with TSCI, with high cure rate. [ABSTRACT FROM AUTHOR]

Cocktail therapy consists of extracorporeal shock wave treatment (ESWT), hyperbaric oxygen therapy (HBO) and alendronate. We hypothesized that this combined therapy may produce better results than ESWT alone when treating hip necrosis. This prospective, randomized study evaluated the effectiveness of cocktail therapy in early hip necrosis, and then compared it to shock wave treatment alone. Sixty-three patients (98 hips) were randomly divided into two groups. Group A consisted of 28 patients (50 hips) who received cocktail therapy, and group B consisted of 35 patients (48 hips) who received only ESWT. Each affected hip was treated with 6,000 shocks of ESWT at 28 kV (equivalent to 0.62 mJ/mm2) in a single session. Cocktail patients also received HBO therapy performed in a multi-place chamber daily for 20 treatments, and they were administered 70 mg of alendronate orally per week for 1 year. The evaluations included clinical assessment, radiograph and MRI. After a minimum of 2-years of follow-up, the overall results showed 74% improved, 16% unchanged and 10% worsened in group A; and 79.2% improved, 10.4% unchanged and 10.4% worsened in group B ( P = 0.717). Total hip replacement (THR) was performed for 10% of group A and 10.4% of group B ( P = 0.946). MRI showed significant reduction in bone marrow edema and a trend of decrease in the size of the lesions in both groups, however, no difference was noted between the two groups. Cocktail therapy is effective for early hip necrosis, but the results are comparable to ESWT in short-term follow up. The joint effects of HBO and alendronate over EWST were not observed. Long-term results are needed to determine whether or not the synergistic effects of ESWT, HBO and alendronate over ESWT alone exist in early hip necrosis. [ABSTRACT FROM AUTHOR]

Amylin is a pancreatic B-cell hormone that plays an important role in the control of nutrient fluxes because it reduces food intake, slows gastric emptying, and reduces postprandial glucagon secretion. These actions seem to depend on a direct effect on the area postrema (AP). Subsequent to area AP activation, the amylin signal is conveyed to the forebrain via distinct relay stations. Within the lateral hypothalamic area, amylin diminishes the expression of orexigenic neuropeptides. Recent studies suggest that amylin may also play a role as a long term, adiposity signal. Similar to leptin or insulin, an infusion of amylin into the brain resulted in lower body weight gain than in controls, irrespective of the starting body weight. Interestingly, preliminary data also suggest that rats fed an energy-dense diet develop resistance to central amylin. In addition to amylin's action to control meal termination and to act as a potential adiposity signal, amylin and its agonist salmon calcitonin have recently been shown to increase energy expenditure under certain conditions. In summary, amylin may be an interesting target as a body weight lowering drug. In fact, recent studies provide evidence that amylin, especially when combined with other anorectic hormones (for example, peptide YY and leptin) has beneficial long-term effects on body weight.International Journal of Obesity (2009) 33, S24–S27; doi:10.1038/ijo.2009.13 [ABSTRACT FROM AUTHOR]

The osteoblast/osteoclast and M1/M2 macrophage ratios play critical roles in delayed fracture healing. Robust osteoblast differentiation and M2 macrophage polarization can substantiality promote fracture repair; however, the combined effect of these strategies has not been previously studied. In this study, we constructed a cocktail therapy to simultaneously regulate the osteoblast/osteoclast and M1/M2 macrophage balance. The cocktail therapy composed of a natural polymer hyaluronic-acid-based hydrogel (HA hydrogel, which has a tissue-adhesive, injectable, self-healing, anti-inflammation profile), engineered endothelial cell-derived exosomes (EC-Exos miR-26a-5p ), and APY29, an IRE-1α inhibitor. This allowed for specific delivery of EC-Exos miR-26a-5p and APY29 for osteoblast/osteoclast and macrophage regulation, respectively. The results suggested that the cocktail therapy exerted pro-fracture repair effects with each of its components established as indispensable. The assessed cocktail therapy provides insight into synergistic strategies and is useful for developing more suitable pro-fracture repair therapy.

The course of idiopathic membranoproliferative glomerulonephritis (MPGN) in 41 Japanese children (21 boys, 20 girls) is reported. The mean follow-up period was 8 years, 9 months; 29 children with MPGN (71%) were identified by school urinary screening; 32 patients had type I MPGN, 2 type II and 7 type III; 10 patients were treated with multiple low-dose cocktail therapy (MLD), 8 with MLD followed by high-dose alternate-day (ALD) prednisolone and 21 with high-dose ALD prednisolone alone. In 1 patient, MPGN progressed to end-stage renal failure. The serum creatinine level in all of the remaining 40 patients was ≤ 1.3 mg/dl at the last follow-up. Urinalysis was normal in 24 (59%). Of the 17 patients who still had urinary abnormalities, 4 had nephrotic syndrome. The incidence of remission of urinary abnormalities was highest in the patients treated with high-dose ALD prednisolone. Rebiopsy was performed in 33 patients, and revealed slight histological improvement in 11 (33%) patients, moderate improvement in 8 (24%), marked improvement in 5 (15%) and deterioration or no improvement in 9 patients (27%). Relatively few side effects of treatment were observed. The superior outcome of the MPGN patients in this compared with other studies may be the result of earlier detection and treatment. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 invades host cells mainly through the interaction of its spike-protein with host cell membrane ACE2. Various antibodies targeting S-protein have been developed to combat COVID-19 pandemic; however, the potential risk of antibody-dependent enhancement and novel spike mutants-induced neutralization loss or antibody resistance still remain. Alternative preventative agents or therapeutics are still urgently needed. In this study, we designed series of peptides with either ACE2 protecting or Spike-protein neutralizing activities. Molecular docking predicted that, among these peptides, ACE2 protecting peptide AYp28 and Spike-protein neutralizing peptide AYn1 showed strongest intermolecular interaction to ACE2 and Spike-protein, respectively, which were further confirmed by both cell- and non-cell-based in vitro assays. In addition, both peptides inhibited the invasion of pseudotype SARS-CoV-2 into HEK293T/hACE2 cells, either alone or in combination. Moreover, the intranasal administration of AYp28 could partially block pseudovirus invasion in hACE2 transgenic mice. Much more importantly, no significant toxicity was observed in peptides-treated cells. AYp28 showed no impacts on ACE2 function. Taken together, the data from our present study predicted promising preventative and therapeutic values of peptides against COVID-19, and may prove the concept that cocktail containing ACE2 protecting peptides and spike neutralizing peptides could serve as a safe and effective approach for SARS-CoV-2 prevention and therapy., Competing Interests: Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Feifei Xie and Jun Tan (J.T.) are cofounders for Anyu Biopharmaceutics, Inc., Hangzhou. J.C., S.L., D.Z., J.T. and F.X. are inventors on a patent application submitted by Anyu Biopharmaceutics, Inc. All other authors report no biomedical financial interests or potential conflicts of interest., (© The author(s).)

Cardiac arrest (CA) results in global ischemia-reperfusion injury damaging tissues in the whole body. The landscape of therapeutic interventions in resuscitation medicine has evolved from focusing solely on achieving return of circulation to now exploring options to mitigate brain injury and preserve brain function after CA. CA pathology includes mitochondrial damage and endoplasmic reticulum stress response, increased generation of reactive oxygen species, neuroinflammation, and neuronal excitotoxic death. Current non-pharmacologic therapies, such as therapeutic hypothermia and extracorporeal cardiopulmonary resuscitation, have shown benefits in protecting against ischemic brain injury and improving neurological outcomes post-CA, yet their application is difficult to institute ubiquitously. The current preclinical pharmacopeia to address CA and the resulting brain injury utilizes drugs that often target singular pathways and have been difficult to translate from the bench to the clinic. Furthermore, the limited combination therapies that have been attempted have shown mixed effects in conferring neuroprotection and improving survival post-CA. The global scale of CA damage and its resultant brain injury necessitates the future of CA interventions to simultaneously target multiple pathways and alleviate the hemodynamic, mitochondrial, metabolic, oxidative, and inflammatory processes in the brain. This narrative review seeks to highlight the current field of post-CA neuroprotective pharmaceutical therapies, both singular and combination, and discuss the use of an extensive multi-drug cocktail therapy as a novel approach to treat CA-mediated dysregulation of multiple pathways, enhancing survival, and neuroprotection., Competing Interests: LB has a grant/research support from Philips Healthcare, the NIH, Nihon Kohden Corp., Zoll Medical Corp, PCORI, BrainCool, and United Therapeutics and owns several issued and pending patents involving the use of medical slurries as human coolant, devices to create slurries, reperfusion cocktails, and measurement of respiratory quotient. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Choudhary, Shoaib, Sohnen, Rolston, Jafari, Miyara, Hayashida, Molmenti, Kim and Becker.)

Glioblastoma is one of the most common malignant tumors in the central nervous system. Due to the high plasticity, heterogeneity and complexity of the tumor microenvironment, these tumors are resistant to almost all therapeutic strategies when they reach an advanced stage. Along with being a unique and effective way to kill cancer cells, tumor-treating fields (TTFields) has emerged as a breakthrough among glioblastoma therapies since the advent of temozolomide (TMZ), and the combination of these treatments has gradually been promoted and applied in the clinic. The combination of TTFields with other therapies is particularly suitable for this type of "cold" tumors and has attracted a large amount of attention from clinicians and researchers in the era of cancer cocktail therapy. Here, we introduced the current treatment regimen for glioblastoma, highlighting the unique advantages of TTFields in the treatment of glioblastoma. Then, we summarized current glioblastoma clinical trials that combine TTFields and other therapies. In addition, the main and potential mechanisms of TTFields were introduced to further understand the rationale for each combination therapy. Finally, we focused on the most advanced technologies applied in glioblastoma research and treatment and the prospect of their combination with TTFields. This review provides a unique overview of glioblastoma treatment., Competing Interests: None., (AJCR Copyright © 2021.)

SARS-CoV-2 antibody therapeutics are being evaluated in clinical and preclinical stages. As of 11 October 2020, 13 human monoclonal antibodies targeting the SARS-CoV-2 spike protein have entered clinical trials with three (REGN-COV2, LY3819253/LY-CoV555, and VIR-7831/VIR-7832) in phase 3. On 9 November 2020, the US Food and Drug Administration issued an emergency use authorization for bamlanivimab (LY3819253/LY-CoV555) for the treatment of mild-to-moderate COVID-19. This review outlines the development of neutralizing antibodies against SARS-CoV-2, with a focus on discussing various antibody discovery strategies (animal immunization, phage display and B cell cloning), describing binding epitopes and comparing neutralizing activities. Broad-neutralizing antibodies targeting the spike proteins of SARS-CoV-2 and SARS-CoV might be helpful for treating COVID-19 and future infections. VIR-7831/7832 based on S309 is the only antibody in late clinical development, which can neutralize both SARS-CoV-2 and SARS-CoV although it does not directly block virus receptor binding. Thus far, the only cross-neutralizing antibody that is also a receptor binding blocker is nanobody VHH-72. The feasibility of developing nanobodies as inhaled drugs for treating COVID-19 and other respiratory diseases is an attractive idea that is worth exploring and testing. A cocktail strategy such as REGN-COV2, or engineered multivalent and multispecific molecules, combining two or more antibodies might improve the efficacy and protect against resistance due to virus escape mutants. Besides the receptor-binding domain, other viral antigens such as the S2 subunit of the spike protein and the viral attachment sites such as heparan sulfate proteoglycans that are on the host cells are worth investigating., (© Published by Oxford University Press on behalf of Antibody Therapeutics 2020.)

Objectives: To evaluate the efficacy of different ways of cocktail analgesic mixture injection on total knee arthroplasty (TKA)., Methods: A total of 50 patients with knee osteoarthritis treated by TKA from July to September 2018 were randomly divided into two groups ( n =25). The Group 1 underwent anterior intra-articular injection before prosthesis implanted while the Group 2 underwent posterior intra-articular injection before prosthesis implanted. Visual Analogue Scale (VAS) of all patients for pain during activity and at rest, maximal flexion degree of the knee at the 48th h and the 72th h after surgery, the time of raise leg, usage rate of patient-controlled analgesia (PCA), and complications were evaluated and analyzed., Results: VAS for pain at rest of patients in the Group 1 was significantly less than that in the Group 2 at the 6th, 12th, and 24th h after surgery (all P <0.05). Maximal flexion degree of the knee at the 48th h and the 72th h after surgery in the Group 1 was better than that in the Group 2 (both P <0.05). The Group 1 costed less time than the Group 2 on the ability to perform an active straight leg raise ( P =0.027)., Conclusions: The anterior intra-articular cocktail analgesic mixture injection can strongly relieve the pain early after TKA, which can improve knee function and achieve painless rehabilitation in most patients, with safety.

Objective: To explore the efficacy and safety of intravenous injection of tranexamic acid (TXA) combined with local use of TXA cocktail in intertrochanteric fracture fixation with proximal femoral nail antirotation (PFNA)., Methods: Patients with intertrochanteric fractures who underwent close reduction and internal fixation with PFNA between February 2018 and March 2019 were enrolled in the study. Among them, 45 patients who met the selection criteria were included in the study and randomly allocated into 3 groups ( n =15). The patients in group A were not received TXA during perioperative period. The patients were intravenously injected of 1.0 g TXA before operation in group B and combined with local use of TXA cocktail during operation in group C. There was no significant difference in the age, gender, body mass index, fracture classification, disease duration, and complications between groups ( P >0.05). The perioperative blood loss and blood transfusion rate, the visual analogue scale (VAS) score before operation and at 12, 24, and 48 hours after operation, the levels of prostaglandin E2 (PGE2) and bradykinin (BK) before operation and at 1 and 3 days after operation, postoperative complications, and the maximum amplitude (MA) of thromboelastogram were recorded and compared between groups., Results: The total blood loss, hidden blood loss, and visible blood loss were significantly lower in groups B and C than those in group A ( P <0.05), and the total blood loss and hidden blood loss were significantly lower in group C than those in group B ( P <0.05). There was no significant difference in the blood transfusion rate, preoperative VAS scores and the levels of PGE2 and BK between groups ( P >0.05). The postoperative VAS scores and the levels of PGE2 and BK were significantly lower in group C than in groups A and B ( P <0.05). There was no significant difference in pre- and post-operative MA of thromboelastogram between groups ( P >0.05). The incidences of postoperative complications were 33.33% (5/15), 20.00% (3/15), and 13.33% (2/15) in groups A, B, and C, respectively, with no significant difference between groups ( χ 2 =1.721, P =0.550)., Conclusion: For intertrochanteric fractures, application of intravenous injection of TXA combined with local use of TXA cocktail in PFNA fixation can reduce perioperative blood loss, relieve pain after operation, and do not increase the risk of complications.

Objective: To evaluate the efficacy and safety of an intraoperative betamethasone periarticular injection in patients undergoing primary unicompartmental knee arthroplasty (UKA). Methods: Seventy patients with knee anteromedial osteoarthritis who underwent the primary unilateral UKA in China-Japan Friendship Hospital from July 2017 to October 2018 were randomized into two groups with random number table. In the group A, an analgesic mixture of morphine, ropivacaine, epinephrine, ketorolac and betamethasone was infiltrated intraoperatively into the soft tissue. While in the group B, a same volume of mixture without betamethasone was injected alternatively. The visual analogue scale (VAS) of pain and analgesic consumption were evaluated to compare the effectiveness of pain control between the two groups. In addition, maximal flexion of the knee andinitial time of the straight leg raising were monitored. Complications were assessed too. The data were compared with independent-sample t test. Results: No significant differences in VAS score was found between the groups at 6 h and 12 h after the operation ( t= -1.154, -1.108, both P> 0.05), but the pain level and analgesic consumption were significantly lower in the group A from 18 h to 72 h post operation ( t= -2.959, -2.808, -2.080, -2.519, -3.378, -3.237, all P< 0.05). The maximal flexion in group A was significantly higher than that in the group B from 1 d to 3 d ( t= 2.985, 4.575, 4.013, all P< 0.05). The straight leg raising ability and incidence of complications were similar between the groups (χ(2)=0.141, 0.000, both P> 0.05). Conclusions: The cocktail analgesics injection containing small dose of betamethasone during UKA can provide effective acute pain control early after the surgery, which is conducive to knee joint function, and it does not increase the incidence of postoperative complications.

The amyloid cascade hypothesis has been dominating drug discovery for Alzheimer's disease (AD) for the last two decades. The failure of the development of effective drugs for slowing down or reversing the progression of AD warrants the AD field to consider out-of-the-box thinking and therapeutic approaches. We propose the multifactorial hypothesis of AD, emphasizing that AD is caused by multiple etiological factors, which may result in common brain pathology and functional consequences through several separate but integrated molecular pathways. More than one etiological factor and mechanistic pathway may be involved in a single individual with sporadic AD, and different individuals may have different etiological factors, involving different mechanisms/pathways. We urge the recognition of the multifactorial nature of AD and the paradigm shift of AD drug development from a single target to multiple targets, either with the multitarget-directed ligands approach or the cocktail therapy approach. We believe that patient stratification and the use of the precision medicine model will also benefit AD drug discovery. [ABSTRACT FROM AUTHOR]