Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Objective To develop a portable heat illness/stroke first-aid kit for on-site first aid of heat illness patients and verify its application effect.Methods The portable heat illness/stroke first-aid kit was composed of a main box,an adjustable telescopic rod,adjustable shoulder straps,universal rollers and a thermal insulation container.The main box made of aluminum alloy material had the inner surface lined with Oxford cloth,which was equipped with an infrared cochlear thermometer,a nebulizer,first aid medicines,heat stroke medicines,a sun umbrella,a cooling blanket,etc;the adjustable telescopic rod was made of aluminum-magnesium alloy;the adjustable shoulder straps was made of high-density nylon webbing;the universal rollers were rubberized and had wheel brakes;the thermal insulation container was located in the lower storage compartment inside the main box,which used polyurethane(PU)material for thermal insulation.The data on on-site first aid of the patients with moderate heat illness or stroke at some institution from 2019 to 2022 were analyzed retrospectively,with the patients treated with the traditional methods enrolled into a control group and the ones with the first-aid kit into an experimental group.The temperature changes at 0,10,20,30,40,50 and 60 min after the start of treatment were investigated to compare the cooling effects of the two groups.Results The heat illness/stroke first-aid kit lowered the patient temperature effectively during the on-site first aid of the patients with moderate heat illness or stroke,with higher cooling speed and effect than the traditional methods,especially at the early stage of treatment.Conclusion The heat illness/stroke first-aid kit with complete functions and easy operation decreases temperature of heat illness patients efficiently,and can be applicable to the scenarios such as field training and outdoors high-temperature operation.[Chinese Medical Equipment Journal,2025,46(9):108-113]

Left ventricular assist device (LVAD) serves as a critical therapeutic option for patients with end-stage heart failure, significantly enhancing survival rates and quality of life. However, LVAD implantation exerts complex and profound effects on right ventricular (RV) function, with RV dysfunction emerging as a key factor influencing the prognosis of LVAD patients. This article systematically reviews the relationship between LVAD and RV function, exploring the importance of RV function in LVAD patients, assessment methods, underlying mechanisms of impact, and strategies for prevention and management. Comprehensive evidence suggests that preoperative evaluation of RV function is crucial for predicting the risk of RV dysfunction, while effective prevention and management rely on preoperative optimization, meticulous intraoperative techniques, rigorous postoperative monitoring, and multidisciplinary collaboration. Furthermore, this review discusses the potential and future directions of emerging technologies, such as improved LVAD designs, biventricular assist devices, gene therapy, and personalized medicine, in ameliorating RV dysfunction. In conclusion, RV function is one of the key determinants of successful LVAD therapy. Through comprehensive assessment, prevention, and management of RV function, coupled with the application of novel technologies, the clinical outcomes of LVAD patients can be further improved.

Objective To develop a portable heat illness/stroke first-aid kit for on-site first aid of heat illness patients and verify its application effect.Methods The portable heat illness/stroke first-aid kit was composed of a main box,an adjustable telescopic rod,adjustable shoulder straps,universal rollers and a thermal insulation container.The main box made of aluminum alloy material had the inner surface lined with Oxford cloth,which was equipped with an infrared cochlear thermometer,a nebulizer,first aid medicines,heat stroke medicines,a sun umbrella,a cooling blanket,etc;the adjustable telescopic rod was made of aluminum-magnesium alloy;the adjustable shoulder straps was made of high-density nylon webbing;the universal rollers were rubberized and had wheel brakes;the thermal insulation container was located in the lower storage compartment inside the main box,which used polyurethane(PU)material for thermal insulation.The data on on-site first aid of the patients with moderate heat illness or stroke at some institution from 2019 to 2022 were analyzed retrospectively,with the patients treated with the traditional methods enrolled into a control group and the ones with the first-aid kit into an experimental group.The temperature changes at 0,10,20,30,40,50 and 60 min after the start of treatment were investigated to compare the cooling effects of the two groups.Results The heat illness/stroke first-aid kit lowered the patient temperature effectively during the on-site first aid of the patients with moderate heat illness or stroke,with higher cooling speed and effect than the traditional methods,especially at the early stage of treatment.Conclusion The heat illness/stroke first-aid kit with complete functions and easy operation decreases temperature of heat illness patients efficiently,and can be applicable to the scenarios such as field training and outdoors high-temperature operation.[Chinese Medical Equipment Journal,2025,46(9):108-113]

Objective:To investigate the clinical value of abdominal adipose volume in predicting early tumor recurrence after resection of hepatocellular carcinoma (HCC).Methods:The retrospective case-control study was conducted. The clinicopathological data of 132 HCC patients with tumor diameter ≤5 cm who were admitted to The First Affiliated Hospital of Army Medical University from December 2017 to October 2019 were collected. There were 110 males and 22 females, aged (51±4)years. All patients underwent resection of HCC. Preoperative computer tomography scanning was performed and the visceral and subcutaneous fats of patients were quantified using the Mimics Research 21.0 software. Based on time to postoperative tumor recurrence patients were divided to two categories: early recurrence and non-early recurrence. Observation indicators: (1) consistency analy-sis; (2) analysis of factors influencing early tumor recurrence after resection of HCC and construction of prediction model. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribu-tion were represented as M( Q1,Q3) or M(range), and comparison between groups was conducted using the Mann-Whitney U test. Count data were expressed as absolute numbers, and comparison between groups was conducted using the chi-square test or Fisher exact probability. Consistency analysis was conducted using the intragroup correlation coefficient (ICC) test. Multivariate analysis was performed using the binary Logistic regression model forward method. Independent risk factors influencing early tumor recurrence after resection of HCC were screened. The area under curve (AUC) of receiver operating characteristic (ROC) curve was applied to select the optimal cut-off value to classify high and low risks of recurrence. The Kaplan-Meier method was used to draw survival curve and calculate survival time. The Log-Rank test was used for survival analysis. Results:(1) Consistency analysis. The consistency ICC of abdominal fat parameters of visceral fat volume (VFV), subcutaneous fat volume, visceral fat area, and subcutaneous fat area measured by 2 radiologists were 0.84, 1.00, 0.86, and 0.94, respectively. (2) Analysis of factors influencing early tumor recurr-ence after resection of HCC and construction of prediction model. All 132 patients were followed up after surgery for 662(range, 292-1 111)days. During the follow-up, there were 52 patients with non-early recurrence and 80 patients with early recurrence. Results of multivariate analysis showed that VFV was an independent factor influencing early tumor recurrence after resection of HCC ( odds ratio=4.07, 95% confidence interval as 2.27-7.27, P<0.05). The AUC of ROC curve based on VFV was 0.78 (95% confidence interval as 0.70-0.85), and the sensitivity and specificity were 72.2 % and 77.4 %, respectively. The optimal cut-off value of VFV was 1.255 dm 3, and all 132 patients were divided into the high-risk early postoperative recurrence group of 69 cases with VFV >1.255 dm 3, and the low-risk early postoperative recurrence group of 63 cases with VFV ≤1.255 dm 3. The disease-free survival time of the high-risk early postoperative recurrence group and the low-risk early post-operative recurrence group were 414(193,702)days and 1 047(620,1 219)days, showing a significant difference between them ( χ2=31.17, P<0.05). Conclusions:VFV is an independent factor influen-cing early tumor recurrence of HCC after resection. As a quantitative indicator of abdominal fat, it can predict the prognosis of HCC patients.

Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P＜0.05).After continuation treatment,the remission rate was 54.59％(202 cases/370 cases),and the recurrence rate was 6.49％(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35％(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.

Objective:To investigate the clinical value of preoperative gadolinium ethoxy-benzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) in predicting microvascular invasion (MVI) and intratumoral tertiary lymphoid structures (TLSs) in hepatocellular carcinoma (HCC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 304 HCC patients who were admitted to The First Affiliated Hospital of Army Medical University and 10 HCC patients who were admitted to The Second Affiliated Hospital of Chongqing Medical University from June 2021 to June 2023 were collected. There were 272 males and 42 females, aged (56±11)years. Using a random number table method, patients were divided into a training set including 220 cases and a validation set including 94 cases in a 7:3 ratio. Among the 314 patients, 106 cases had MVI and TLSs-positive HCC (MT-HCC), and 208 cases had non-MT-HCC. All patients underwent preoperative Gd-EOB-DTPA-enhanced MRI and radical resection. Observation indicators: (1) clinicopathological characteristics of MT-HCC and non-MT-HCC patients; (2) imaging characteristics of MT-HCC and non-MT-HCC patients; (3) imaging features associated with MT-HCC diagnosis; (4) nomogram predictive model construction and evaluation for MT-HCC. Comparison of measurement data with normal distribution between groups was analyzed using the t test. Comparison of measurement data with skewed distribution between groups was analyzed using the nonpara-meter rank sum test. Univariate analysis was conducted using the corresponding statistical methods based on data type. Multivariate analysis was conducted using the logistic regression model. A nomo-gram predictive model was constructed based on results of multivariate analysis, and receiver operating characteristic (ROC) curves were plotted to evaluate the model's performance with the area under curve (AUC). Calibration curve and decision curve analyses were used to assess the calibration and clinical validity of nomogram predictive model. Results:(1) Clinicopathological characteristics of MT-HCC and non-MT-HCC patients. In the training set, there were significant differences between MT-HCC and non-MT-HCC patients in terms of age, white blood cell count, and alpha fetoprotein level ( t=2.488, Z=-2.515, χ2=4.014, P<0.05). (2) Imaging characteristics of MT-HCC and non-MT-HCC patients. In the training set, there were significant differences in tumor morphology, intratumoral hemorrhage, peritumoral abnormal enhancement in arterial phase, capsule presence, intratumoral necrosis or ischemia >20%, intratumoral necrosis or ischemia >50%, peritumoral hypointensity in the hepatobiliary phase, intravascular tumor thrombus, arterial phase rim-like hyperenhancement, and mosaic architecture between MT-HCC and non-MT-HCC patients ( χ2=8.811, 5.586, 13.962, 31.616, 10.154, 4.835, 5.111, 14.425, 7.112, 5.526, P<0.05). (3) Imaging features associated with MT-HCC diagnosis. Results of multivariate analysis identified the absence of intratumoral hemorrhage, incom-plete capsule, and mosaic architecture as independent risk factors for diagnosing MT-HCC ( hazard ratio=3.846, 7.827, 2.345, P<0.05). (4) Nomogram predictive model construction and evaluation for MT-HCC. A nomogram predictive model for MT-HCC was constructed based on the independent risk factors (absence of intratumoral hemorrhage, incomplete capsule, and mosaic architecture) iden-tified in the multivariate analysis. The ROC curve analysis showed that AUC of nomogram predictive model was 0.778 (95% confidence interval as 0.714-0.843), with sensitivity and specificity of 0.857 and 0.573 in the training set. In the validation set, the area under the curve, sensitivity, and specifi-city were 0.825 (95% confidence interval as 0.745-0.926), 0.655, and 0.877, respectively. The calibra-tion curves for both the training set and the validation set closely aligned with the standard curve, indicating high calibration accuracy. The decision curve analysis demonstrated net clinical benefits at thresholds of 0.130-0.690 in the training set and 0.060-0.750 in the validation set. Conclusions:The absence of intratumoral hemorrhage, incomplete capsule, and mosaic architecture are independent risk factors for diagnosing MT-HCC. A nomogram model based on imaging features can predict MT-HCC in HCC patients.

Objective:To investigate the clinical value of preoperative gadolinium ethoxy-benzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) in predicting microvascular invasion (MVI) and intratumoral tertiary lymphoid structures (TLSs) in hepatocellular carcinoma (HCC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 304 HCC patients who were admitted to The First Affiliated Hospital of Army Medical University and 10 HCC patients who were admitted to The Second Affiliated Hospital of Chongqing Medical University from June 2021 to June 2023 were collected. There were 272 males and 42 females, aged (56±11)years. Using a random number table method, patients were divided into a training set including 220 cases and a validation set including 94 cases in a 7:3 ratio. Among the 314 patients, 106 cases had MVI and TLSs-positive HCC (MT-HCC), and 208 cases had non-MT-HCC. All patients underwent preoperative Gd-EOB-DTPA-enhanced MRI and radical resection. Observation indicators: (1) clinicopathological characteristics of MT-HCC and non-MT-HCC patients; (2) imaging characteristics of MT-HCC and non-MT-HCC patients; (3) imaging features associated with MT-HCC diagnosis; (4) nomogram predictive model construction and evaluation for MT-HCC. Comparison of measurement data with normal distribution between groups was analyzed using the t test. Comparison of measurement data with skewed distribution between groups was analyzed using the nonpara-meter rank sum test. Univariate analysis was conducted using the corresponding statistical methods based on data type. Multivariate analysis was conducted using the logistic regression model. A nomo-gram predictive model was constructed based on results of multivariate analysis, and receiver operating characteristic (ROC) curves were plotted to evaluate the model's performance with the area under curve (AUC). Calibration curve and decision curve analyses were used to assess the calibration and clinical validity of nomogram predictive model. Results:(1) Clinicopathological characteristics of MT-HCC and non-MT-HCC patients. In the training set, there were significant differences between MT-HCC and non-MT-HCC patients in terms of age, white blood cell count, and alpha fetoprotein level ( t=2.488, Z=-2.515, χ2=4.014, P<0.05). (2) Imaging characteristics of MT-HCC and non-MT-HCC patients. In the training set, there were significant differences in tumor morphology, intratumoral hemorrhage, peritumoral abnormal enhancement in arterial phase, capsule presence, intratumoral necrosis or ischemia >20%, intratumoral necrosis or ischemia >50%, peritumoral hypointensity in the hepatobiliary phase, intravascular tumor thrombus, arterial phase rim-like hyperenhancement, and mosaic architecture between MT-HCC and non-MT-HCC patients ( χ2=8.811, 5.586, 13.962, 31.616, 10.154, 4.835, 5.111, 14.425, 7.112, 5.526, P<0.05). (3) Imaging features associated with MT-HCC diagnosis. Results of multivariate analysis identified the absence of intratumoral hemorrhage, incom-plete capsule, and mosaic architecture as independent risk factors for diagnosing MT-HCC ( hazard ratio=3.846, 7.827, 2.345, P<0.05). (4) Nomogram predictive model construction and evaluation for MT-HCC. A nomogram predictive model for MT-HCC was constructed based on the independent risk factors (absence of intratumoral hemorrhage, incomplete capsule, and mosaic architecture) iden-tified in the multivariate analysis. The ROC curve analysis showed that AUC of nomogram predictive model was 0.778 (95% confidence interval as 0.714-0.843), with sensitivity and specificity of 0.857 and 0.573 in the training set. In the validation set, the area under the curve, sensitivity, and specifi-city were 0.825 (95% confidence interval as 0.745-0.926), 0.655, and 0.877, respectively. The calibra-tion curves for both the training set and the validation set closely aligned with the standard curve, indicating high calibration accuracy. The decision curve analysis demonstrated net clinical benefits at thresholds of 0.130-0.690 in the training set and 0.060-0.750 in the validation set. Conclusions:The absence of intratumoral hemorrhage, incomplete capsule, and mosaic architecture are independent risk factors for diagnosing MT-HCC. A nomogram model based on imaging features can predict MT-HCC in HCC patients.

Objective:To investigate the expression of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway in patients with acute myeloid leukemia (AML) and its relationship with clinical features and prognosis, and to examine its effect on PD-1-positive natural killer (NK) cells against AML cells in vitro.Methods:The bone marrow samples of 65 AML patients and the peripheral blood of 32 AML patients diagnosed in Affiliated Cancer Hospital of Zhengzhou University from July 2019 to December 2020 were prospectively collected, and the peripheral blood of 24 healthy people was taken as healthy control. The expression level of PD-L1 in bone marrow tumor cells and expression level of PD-1 in peripheral blood NK cells were detected by flow cytometry. The correlations of PD-1 expression in bone marrow tumor cells and PD-1 expression in NK cells with the clinicopathological features, curative effect and prognosis of patients were analyzed. Flow cytometry was used to detect the expression level of PD-L1 in AML cell line THP-1 (target cells) and the expression level of PD-L1 in NK cell line NKL (effector cells). THP-1 cells treated with and without 25 μmol/L of PD-L1 inhibitor fraxinellone were used as experimental group and control group, and co-cultured with NKL cells at different effector-to-target ratios. The apoptosis of THP-1 cells and the expression of NKG2D in NKL cells were detected by flow cytometry, the cell proliferation status was detected by CCK-8 and the cell proliferation inhibition rate was calculated; the levels of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in the supernatant of co-culture system were detected by enzyme-linked immunosorbent assay (ELISA).Results:The proportion of AML patients with PD-L1-positive expression in bone marrow tumor cells was higher than that in the healthy control group [38.5% (25/65) vs. 8.3% (2/24), P = 0.029]. The proportion of AML patients with PD-1-positive expression in peripheral blood NK cells was higher than that in the healthy control group [40.6% (13/32) vs. 12.5% (3/24), P = 0.035]. There were no statistical differences in sex, age, hemogram, proportion of primordial cells, risk stratification, chromosomal karyotype, gene mutation (except NPM1 gene), fusion gene and French-American-British cooperative group (FAB) typing between patients with PD-L1 positive and negative in bone marrow tumor cells and between patients with PD-1 positive and negative in peripheral blood NK cells (all P > 0.05). In relapsed/refractory patients, the proportion of patients with PD-L1-positive expression in bone marrow tumor cells was higher than that in newly treated patients [58.8% (10/17) vs. 31.2% (15/48), P = 0.045]. There was no significant difference in the proportion of patients with PD-1-positive expression in peripheral blood NK cells between relapsed/refractory patients and newly treated patients [(38.5% (5/13) vs. 42.1% (8/19), P = 0.837]. There was no statistical difference in complete remission (CR) rate between PD-L1 positive and negative patients [69.6% (16/23) vs. 74.3% (26/35), P > 0.05]. There was no statistical difference in CR rate between PD-1 positive and negative patients [66.7% (8/12) vs. 70.6% (12/17), P > 0.05]. There was no statistical difference in recurrence rate after CR between PD-L1 positive and negative patients [12.5% (2/16) vs. 19.2% (5/26), P > 0.05]. There was no statistical difference in recurrence rate after CR between PD-1 positive and negative patients [25.0% (2/8) vs. 16.7% (2/12), P > 0.05]. Flow cytometry showed that the positive rate of PD-1 in NKL cells was (67±6)% and the positive rate of PD-L1 in THP-1 cells was (85±5)%. After co-culture with NKL cells, the apoptotic rate and proliferation inhibition rate of THP-1 cells were higher in the experimental group compared with the control group, the expression of NKG2D on the surface of NKL cells was elevated, and the levels of IFN-γ and TNF-α in the co-culture supernatant were increased. Conclusions:In AML patients, the expression of PD-L1 in bone marrow tumor cells is high, and the expression of PD-1 in peripheral blood NK cells is also high. The expression of PD-L1 in bone marrow tumor cells of relapsed/refractory AML patients is higher than that of newly treated patients. Inhibition of PD-L1 expression in THP-1 cells can enhance the tumor killing activity of NKL cells in vitro. The mechanism may be that inhibition of PD-L1 expression in THP-1 cells up-regulates the expression of NKL cell activated receptor NKG2D and promotes the secretion of IFN- γ and TNF- α.

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.
Female ; Humans ; Male ; Aged ; Middle Aged ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Prognosis ; Lymphoma, B-Cell ; Immunohistochemistry ; Immunoglobulin Heavy Chains/therapeutic use*